Compounds useful in the treatment of inflammatory diseases

ABSTRACT

There are provided according to the invention, novel compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X a, b, and Z are as defined in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.

[0001] This invention relates to novel chemical compounds, processes fortheir preparation, pharmaceutical formulations containing them and theiruse in therapy. Inflammation is a primary response to tissue injury ormicrobial invasion and is characterised by leukocyte adhesion to theendothelium, diapedesis and activation within the tissue. Leukocyteactivation can result in the generation of toxic oxygen species (such assuperoxide anion), and the release of granule products (such asperoxidases and proteases). Circulating leukocytes include neutrophils,eosinophils, basophils, monocytes and lymphocytes. Different forms ofinflammation involve different types of infiltrating leukocytes, theparticular profile being regulated by the profile of adhesion molecule,cytokine and chemotactic factor expression within the tissue.

[0002] The primary function of leukocytes is to defend the host frominvading organisms, such as bacteria and parasites. Once a tissue isinjured or infected, a series of events occurs which causes the localrecruitment of leukocytes from the circulation into the affected tissue.Leukocyte recruitment is controlled to allow for the orderly destructionand phagocytosis of foreign or dead cells, followed by tissue repair andresolution of the inflammatory infiltrate. However in chronicinflammatory states, recruitment is often inappropriate, resolution isnot adequately controlled and the inflammatory reaction causes tissuedestruction. There is increasing evidence that the bronchialinflammation which is characteristic of asthma represents a specialisedform of cell-mediated immunity, in which cytokine products, such as IL-4and IL-5 released by Th2 T lymphocytes, orchestrate the accumulation andactivation of granulocytes, in particular eosinophils and to a lesserextent basophils. Through the release of cytotoxic basic proteins,pro-inflammatory mediators and oxygen radicals, eosinophils generatemucosal damage and initiate mechanisms that underlie bronchialhyperreactivity. Therefore, blocking the recruitment and activation ofTh2 cells and eosinophils is likely to have anti-inflammatory propertiesin asthma. In addition, eosinophils have been implicated in otherdisease types such as rhinitis, eczema, irritable bowel syndrome andparasitic infections.

[0003] Chemokines are a large family of small proteins which areinvolved in trafficking and recruitment of leukocytes (for review seeLuster, New Eng. J. Med., 338, 436-445 (1998)). They are released by awide variety of cells and act to attract and activate various celltypes, including eosinophils, basophils, neutrophils, macrophages, T andB lymphocytes. There are two major families of chemokines, CXC-(α) andCC-(β) chemokines, classified according to the spacing of two conservedcysteine residues near to the amino terminus of the chemokine proteins.Chemokines bind to specific cell surface receptors belonging to thefamily of G-protein-coupled seven transmembrane-domain proteins (forreview see Luster, 1998). Activation of chemokine receptors results in,amongst other responses, an increase in intracellular calcium, changesin cell shape, increased expression of cellular adhesion molecules,degranulation and promotion of cell migration (chemotaxis).

[0004] To date, 9 members of CC chemokine receptors have been identified(CCR-1 to 9). Of particular importance to the current invention is theCC-chemokine receptor-3 (CCR-3), which is predominantly expressed oneosinophils, and also on basophils, mast cells and Th2 cells (Luster,1998). Chemokines that act at CCR-3, such as RANTES, MCP-3 and MCP-4,are known to recruit and activate eosinophils. Of particular interestare eotaxin and eotaxin-2, which specifically bind to CCR-3. Thelocalization and function of CCR-3 chemokines indicate that they play acentral role in the development of allergic diseases such as asthma.Thus, CCR-3 is specifically expressed on all the major cell typesinvolved in inflammatory allergic responses. Chemokines that act atCCR-3 are generated in response to inflammatory stimuli and act torecruit these cell types to sites of inflammation, where they causetheir activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887(1994), Lloyd et al., J. Exp. Med., 191, 265-273 (2000)). In addition,anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interactionwith eosinophils (Heath, H. et al., (1997) J. Clin. Invest. 99 (2),178-184), while an antibody for the CCR-3 specific chemokine, eotaxin,reduced both bronchial hyperreactivity and lung eosinophilia in ananimal model of asthma (Gonzalo et al., J. Exp. Med., 188, 157-167(1998). Thus, many lines of evidence indicate that antagonists at theCCR-3 receptor are very likely to be of therapeutic use for thetreatment of a range of inflammatory conditions.

[0005] A number of patent applications relating to CCR-3 antagonistshave published before the filing date of this application. For example,EP 0 903 349, FR 2785902, WO 00/29377, WO 00/31032 and WO 00/31033 (allin the name of F. Hoffmann-La-Roche AG) disclose pyrrolidine, piperidineand piperazine based compounds which are all distinct from the compoundsof the present invention.

[0006] WO 99/55324, WO 00/04003, WO 00/27800, WO 00/27835, WO 00/27843,WO 00/41685 and WO 00/53172 (all in the name of SmithKline BeechamCorporation) describe a variety of compounds as CCR-3 antagonists whichare unrelated to the compounds of the present invention.

[0007] WO 00/34278 (Toray Industries Inc.) describe fused triazoloderived compounds as chemokine inhibitors.

[0008] WO 00/35449, WO 00/35451, WO 00/35452, WO 00/35453, WO 00/35454,WO 00/35876 and WO 00/35877 (Du Pont Pharmaceuticals Company) describeN-ureidoalkyl and heterocyclic piperidine compounds as CCR-3antagonists.

[0009] WO 00/51607 and WO 00/51608 (Merck & Co. Inc.) describe a seriesof pyrrolidine modulators of chemokine receptor activity.

[0010] WO 00/53600 (Banyu Pharmaceutical Co. Ltd.) describes piperidinederivatives as inhibitors at the CCR-3 receptor.

[0011] WO 01/14333 (AstraZeneca UK Ltd.) describe substituted piperidinecompounds as modulators of chemokine receptor activity.

[0012] EP 0 760 362 (Nisshin Flour Milling Co. Ltd.) describesmorpholinoalkylurea derivatives which are disclosed as being useful inthe treatment of digestive tract diseases.

[0013] JP 04208267A (Mitsui Seiyaku Kogyo KK) also describesmorpholinoalkylurea derivatives which are disclosed as being useful asantiemetics, for activating peristalsis and amelioratinggastrointestinal function.

[0014] EP 243959A (Dainippon Pharm KK) describes O-substitutedN-morpholinyl-alkyl-benzamide derivatives useful as gastrointestinalmotility enhancing agents.

[0015] JO 1117-882A (Dainippon Pharm KK) describes heterocyclicmorpholinyl alkylenyl carboxamide derivatives useful as anti-emetics.

[0016] WO 00/71518 (Sepracor Inc) describes morpholinoalkylamidederivatives useful in the treatment of pain, drug addiction andtinnitus.

[0017] WO 97/48695 and WO 97/48397 (Klinge Pharma Gmbh) describe pyridylalkane, alkene and/or alkyne acid amide compounds useful as cytostatic,immunomodulatory or immuno-suppressive agents.

[0018] Kato et al., (1992) Chem. Pharm. Bull. 40(3), 652-660, Kato etal., (1991) J. Med. Chem. 34(2), 616-624 and Kato et al., (1990) J. Med.Chem. 33(5), 1406-1413 describe a series of morpholine benzamides whichare disclosed as being selective and potent gastrokinetic agents.

[0019] We have now found a novel group of CCR-3 antagonist compoundswhich block migration/chemotaxis of eosinophils, consequently effectinganti-inflammatory properties. These compounds are therefore of potentialtherapeutic benefit, especially in providing protection from eosinophil,basophil and Th2-cell-induced tissue damage in diseases where such celltypes are implicated, particularly allergic diseases, including but notlimited to bronchial asthma, allergic rhinitis and atopic dermatitis.

[0020] In addition to a key role in inflammatory disorders, chemokinesand their receptors also play a role in infectious disease. Mammaliancytomegaloviruses, herpes viruses and pox viruses express chemokinereceptor homologues, which can be activated by human CC chemokines suchas RANTES and MCP-3 (for review see Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748, 1997). In addition, human chemokine receptors,such as CXCR-4, CCR-5 and CCR-3, can act as co-receptors for theinfection of mammalian cells by microbes such as human immunodeficiencyviruses (HIV). CCR-3 serves as a co-receptor for certain clinicalstrains of HIV-1 and facilitates viral entry (e.g Choe, H. et al, Cell,1996, 85, 1135-1148). A key ligand for CCR-3, eotaxin, blocked theprocess of HIV entry. Thus, chemokine receptor antagonists, includingCCR-3 antagonists, may be useful in blocking infection of CCR-3expressing cells by HIV or in preventing the manipulation of immunecellular responses by viruses such as cytomegaloviruses.

[0021] Thus, according to one aspect of the invention, we providecompounds of formula (I):

[0022] wherein:

[0023] R¹ represents C₁ alkyl, C₂₋₄ alkenyl, C₂₋₆ alkynyl, aryl-Y¹—,heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—,heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—,aryl-SO₂—Y¹—, C₁₋₆ alkyl-G-Y¹—, heteroaryl-G-aryl-Y¹—, J¹-SO₂—Y¹—,R¹⁷O(CO)—C₂₋₆ alkenyl-Y¹—, R¹⁷NHCO—Y¹—, R¹⁷NHSO₂—Y¹—, C₂₋₆ alkynyl-Y¹—,C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—,M-Y¹—, J¹-Y¹—, J¹-CO—Y¹—, aryl-CO—Y¹— or C₃₋₈ cycloalkyl-Y¹— or C₃₋₈cycloalkenyl-Y¹—, which C₂₋₆ alkynyl and C₂₋₆ alkynyl-Y¹ may beoptionally substituted with a —OR¹⁷ group, which C₂₋₆ alkenyl may beoptionally substituted by one or more —COOR¹⁷ groups and whichcycloalkyl or cycloalkenyl may be optionally substituted by one or morehydroxyl or C₁₋₄ alkyl groups;

[0024] R² represents hydrogen or C₁₋₄ alkyl optionally substituted by ahydroxy group;

[0025] R³ represents hydrogen or C₁₋₆ alkyl;

[0026] or R¹ and R² may together with the nitrogen atom to which theyare attached form a group of formula J² wherein said nitrogen atomsubstitutes for either X¹ or X²;

[0027] t represents 0 or 1.

[0028] X represents ethylene or a group of formula CR^(e)R^(f) whereinR^(e) and R^(f) independently represent hydrogen or C₁₋₄ alkyl or R^(e)and R^(f) may together with the carbon atom to which they are attachedform a C₃₋₈ cycloalkyl group;

[0029] R⁴ and R⁵ independently represent hydrogen or C₁₋₄ alkyl;

[0030] Z represents a bond, CO, SO₂, CR¹⁰R⁷(CH₂)_(n), (CH₂)_(n)CR¹⁰R⁷,CHR⁷(CH₂)_(n)O, CHR⁷(CH₂)_(n)S, CHR⁷(CH₂)_(n)OCO, CHR⁷(CH₂)_(n)CO,COCHR⁷(CH₂)_(n) or SO₂CHR⁷(CH₂)_(n);

[0031] R⁶ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, aryl, heteroaryl,aryl-C₂₋₆ alkenyl-, —CN or a group of formula —Y²-J³;

[0032] R⁷ represents hydrogen, C₁₋₄alkyl, CONR⁸R⁹ or COOC₁₋₆ alkyl;

[0033] a and b represent 1 or 2, such that a+b represents 2 or 3;

[0034] G represents —SO₂—, —SO₂NR¹⁸—, —NR¹⁸SO₂—, —NR¹⁸CO—, CO or—CONR¹⁸—;

[0035] n represents an integer from 0 to 4;

[0036] M represents a C. cycloalkyl or C₃₋₈ cycloalkenyl group fused toa monocyclic aryl or monocyclic heteroaryl group;

[0037] J¹, J² and J³ independently represent a moiety of formula (K):

[0038] wherein X¹ represents oxygen, NR¹¹ or sulphur, X² represents CH₂,oxygen, NR¹² or sulphur, m¹ represents an integer from 1 to 3 and m²represents an integer from 1 to 3, provided that m¹+m² is in the rangefrom 3 to 5, also provided that when both X¹ and X² represent oxygen,NR¹¹, NR¹² or sulphur, m¹ and m² must both not equal less than 2,wherein K is optionally substituted by one or more (eg. 1 or 2)—Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —COC₃₋₈ cycloalkyl,—Y³—CO-heteroaryl, —C₁₋₆ alkyl, —Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆alkyl,—Y³—W, —Y³—CO—W, —Y³—NR¹⁵R¹⁶, —Y³—CONR¹⁵R¹⁶, hydroxy, oxo,—Y³—SO₂NR¹⁵R¹⁶, —Y³—SO₂C₁₋₆ alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl,—Y³—NR¹³C₁₋₆ alkyl, —Y³—NR¹³SO₂C₁₋₆alkyl, —Y³—NR¹³CONR¹⁵R¹⁶,—Y³—NR¹³COOR¹⁴ or —Y³—OCONR¹⁵R¹⁶ groups, and is optionally fused to amonocyclic aryl or heteroaryl ring;

[0039] R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently representhydrogen or C₁₋₆ alkyl;

[0040] R¹⁵ and R¹⁶ independently represent hydrogen or C₁₋₆ alkyl or R¹⁵and R¹⁶ together with the nitrogen atom to which they are attached mayform a morpholine, piperidine or pyrrolidine ring;

[0041] R¹⁷ and R¹⁸ independently represent hydrogen or C₁₋₆ alkyl;

[0042] W represents a saturated or unsaturated, non-aromatic 5-7membered ring containing between 1 and 3 heteroatoms selected fromnitrogen, oxygen or sulphur, optionally substituted with one or moreC₁₋₆ alkyl, halogen or hydroxy groups;

[0043] Y¹, Y² and Y³ independently represent a bond or a group offormula —CH₂)_(p)CR^(c)R^(d)(CH₂)_(q)— wherein R^(c) and R^(d)independently represent hydrogen or C₁₋₄ alkyl or R^(c) and R^(d) maytogether with the carbon atom to which they are attached form a C₃₋₈cycloalkyl group, and p and q independently represent an integer from 0to 5 wherein p+q is an integer from 0 to 5;

[0044] and salts and solvates thereof.

[0045] Specific groups of compounds of formula (I) which may bementioned are those as defined above with the proviso that the compoundof formula (I) is not a compound of formula (I)^(a):

[0046] wherein R² represents hydrogen or lower alkyl (specifically C₁₋₄alkyl); R^(3′) represents hydrogen; X¹ represents methylene or ethylene;a′ and b′ both represent 1; R^(4′) and R^(5′) both represent hydrogen;and wherein the moiety -Z′-R^(6′) represents halobenzyl (compounds offormula (I)^(a) are described in JP 04208267A); and/or

[0047] the proviso that the compound of formula (I) is not a compound offormula (I)^(b):

[0048] wherein R^(1″) represents a hydrogen atom, a C₁₋₆ alkyl group, aC₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyl C₁₋₄ alkyl group, an aryl groupor an arylC₁₋₄ alkyl group (particularly wherein aryl represents phenylor naphthyl) in which the aryl moiety of the aryl group or arylC₁₋₄alkyl group may be-optionally substituted with a halogen atom, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxycarbonyl group or anamino group; R^(2″) represents hydrogen; R^(3″) represents hydrogen orC₁₋₆alkyl; X″ represents methylene; a″ and b″ both represent 1; R^(4″)and R^(5″) both represent hydrogen; and wherein the moiety -Z″-R^(6″)represents a C₁₋₆ alkyl group, an arylC₁₋₄ alkyl group (particularlywherein aryl represents phenyl or naphthyl), a heteroarylC₁₋₄ alkylgroup (particularly wherein heteroaryl represents 2-pyridyl, 3-pyridyl,4-pyridyl or 1H-indol-3-yl), an aryloxyC₂₋₅ alkyl group or apyrrolidinylcarbonylC₁₋₄ alkyl group in which the aryl moiety of thesaid groups may be optionally substituted with a halogen atom, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxycarbonyl group or anamino group (compounds of formula (I)^(b) are described in EP0760362A1).

[0049] A preferred set of compounds include compounds of formula (I)wherein R¹ represents C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl-Y¹—,heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—,heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—,aryl-SO₂—Y¹—, C₁₋₆ alkyl-G-Y′-, J¹—SO₂-Y¹—, R¹⁷O(CO)—C₂₋₆ alkenyl-Y¹—,C₂₋₆ alkynyl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-O—Y¹—, C₁₋₆alkyl-SO₂—Y¹—, M-Y′-, J¹-Y¹—, J¹-CO—Y¹—, aryl-CO—Y¹— or C₃₋₈cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which C₂₋₆ alkynyl and C₂₋₆alkynyl-Y¹ may be optionally substituted with a —OR¹⁷ group and whichcycloalkyl or cycloalkenyl may be optionally substituted by one or morehydroxyl or C₁₋₆ alkyl groups;

[0050] R² represents hydrogen or C₁₋₆ alkyl; and

[0051] J¹, J² and J³ independently represent a moiety of formula (K):

[0052] wherein X¹ represents oxygen, NR¹¹ or sulphur, X² represents CH₂,oxygen, NR¹² or sulphur, m¹ represents an integer from 1 to 3 and m²represents an integer from 1 to 3, provided that m¹+m² is in the rangefrom 3 to 5, also provided that when both X¹ and X² represent oxygen,NR¹¹, NR¹² or sulphur, m¹ and m² must both not equal less than 2,wherein K is optionally substituted by one or more (eg. 1 or 2)—Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₆alkyl,—Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹⁵R¹⁶,—Y³—CONR¹⁵R¹⁶, hydroxy, oxo, —Y³—SO₂NR¹⁵R¹⁶, —Y³—SO₂C₁₋₆ alkyl,—Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³—NR¹³C₁₋₆ alkyl, —Y³—NR¹³SO₂C₁₋₆alkyl, —Y³—NR¹³CONR¹⁵R¹⁶, —Y³—NR¹³COOR¹⁴ or —Y³—OCONR¹⁵R¹⁶ groups, andis optionally fused to a monocyclic aryl or heteroaryl ring;

[0053] A preferred subset of compounds include compounds of formula (I)wherein R¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl-Y¹—,heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—,heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂—alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹—,—Y¹-J¹, —Y¹—CO-J¹ or C₃₋₈ cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, whichcycloalkyl or cycloalkenyl may be optionally substituted by one or morehydroxyl or C₁ alkyl groups;

[0054] R² represents hydrogen or C₁₋₆ alkyl;

[0055] Z represents a bond, CO, CR¹⁰R⁷(CH₂)_(n), CHR⁷(CH₂)_(n)O,CHR⁷(CH₂)_(n)S, CHR⁷(CH₂)_(n)OCO, CHR⁷(CH₂)_(n)CO; and

[0056] J¹, J² and J³ independently represent a moiety of formula (K):

[0057] wherein X¹ represents oxygen, nitrogen, NR¹¹ or sulphur, X²represents CH₂, oxygen, nitrogen, NR¹² or sulphur, m¹ represents aninteger from 1 to 3, m² represents an integer from 1 to 3, provided thatm¹+m² is in the range from 3 to 5, also provided that when X² representsoxygen, nitrogen, NR¹² or sulphur, m¹ and m² must both not equal lessthan 2, wherein K is optionally substituted by one or more (eg. 1 or 2)—Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₆ alkyl,—Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹⁵R¹⁶,—Y³—CONR¹⁵R¹⁶, hydroxy, oxo, —Y³—SO₂NR¹⁵R¹⁶, —Y³—SO₂C₁₋₆alkyl,—Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³—NR¹³C₁₋₆alkyl, —Y³—NR¹³SO₂C₁₋₆alkyl, —Y³—NR¹³CONR¹⁵R¹⁶, —Y³—NR¹³COOR¹⁴ or —Y³—OCONR¹⁵R¹⁶ groups, andis optionally fused to a monocyclic aryl or heteroaryl ring;

[0058] References to ‘aryl’ include references to monocyclic carbocyclicaromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings(e.g. naphthyl) and references to ‘heteroaryl’ include references tomono- and bicyclic heterocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur. References to‘heteroaryl’ may also be extended to include references to mono- andbicyclic heterocyclic aromatic rings containing 4 hetero atoms selectedfrom nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclicaromatic rings include e.g. pyridinyl, pyrimidinyl, thiophenyl, furanyl,pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl.Further examples of monocyclic heterocyclic aromatic rings includepyrazinyl, tetrazolyl or imidazolyl. Examples of bicyclic heterocyclicaromatic rings include eg. quinolinyl or indolyl. Further examples ofbicyclic heterocyclic aromatic rings include benzimidazolyl. Yet furtherexamples of bicyclic heterocyclic aromatic rings includedihydrobenzofuranyl and pyrrolopyridinyl. Carbocyclic and heterocyclicaromatic rings may be optionally substituted, e.g. by one or more Conalkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino,W, —N(CH₃)₂, —NHCOC₁₋₄ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHF₂,—SCF₃, —CONR¹⁹R²⁰, —SO₂NR¹⁹R²⁰ (wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl), —NHSO₂CH₃, —SO₂CH₃or —SCH₃ groups. A further substituent of carbocyclic and heterocyclicaromatic rings may be —COOH. Yet further substituents of carbocyclic andheterocyclic aromatic rings may be —CH₂N(CH₃)₂ or one or more —SHgroups, wherein it will be appreciated that said group may tautomeriseto form an ═S group.

[0059] Examples of group M include tetrahydronaphthalenyl.

[0060] Examples of group W include piperidinyl, pyrrolidinyl,morpholinyl and piperazinyl which may be optionally substituted with oneor more C₁₋₆ alkyl, halogen, or hydroxy groups.

[0061] Examples of group J¹ include N—(COOCH₂CH₃)-piperidin-4-yl,N—(CH₃)-piperidin-4-yl, N—(COCH₃)-piperidin-4-yl, pyrrolidin-1-yl,tetrahydropyran-4-yl or N-morpholinyl. Further examples of group J¹include N-(cyclopropylcarbonyl)-piperidin-4-yl,N-(methylsulphonyl)-piperidin-4-yl, thiopyranyl and tetrahydrothienyl.

[0062] Examples of group J² include (4-phenyl)-piperidin-1-yl,(4-COOCH₂CH₃)-piperazin-1-yl,(2-(3-hydroxy-pyrrolidin-1-yl-methyl))-piperidin-1-yl, N-morpholinyl,(4—N(CH₃)₂)-piperidin-1-yl, (4-(3-fluorophenyl))-piperazin-1-yl,(4-(4-fluorophenyl))-piperazin-1-yl, (4-pyrimidinyl)-piperazin-1-yl,(4-CH₃)-piperazin-1-yl, (4-CONH₂)-piperidin-1-yl,(3,3-dimethyl)-piperidin-1-yl, (4-COCH₃)-piperazin-1-yl,(4-(1-pyrrolidinyl-carbonylmethyl))-piperazin-1-yl,(4-hydroxy)-piperidin-1-yl, (4-methyl)-piperidin-1-yl,(4-(2-furanyl-carbonyl))-piperazin-1-yl, (4-benzyl)-piperazin-1-yl or(3-CH₃SO₂CH₂—)-morpholin-1-yl. Further examples of group J² includethiomorpholinyl, pyrrolidinyl and benzazepinyl.

[0063] Examples of group J³ include indolinyl, which may be optionallysubstituted.

[0064] References to alkyl include references to both straight chain andbranched chain aliphatic isomers of the corresponding alkyl. It will beappreciated that references to alkylene and alkoxy shall be interpretedsimilarly.

[0065] References to C₃₋₈ cycloalkyl include references to all alicyclic(including branched) isomers of the corresponding alkyl.

[0066] Preferably, R¹ represents C₁₋₄ alkyl (particularly propyl), C₂₋₆alkenyl (particularly wherein said C₂₋₆ alkenyl is substituted by one ormore —COOR¹⁷ groups, eg. —HC═CH—COOH), C₂₋₆ alkynyl, aryl-Y¹—,heteroaryl-Y¹— (particularly wherein heteroaryl represents thiazolyl,indolyl, furanyl, dihydrobenzofuran, oxoimidazolyl, isoxazolyl, thienyl,thioxodihydroimidazolyl, tetrazolyl, pyrazinyl, pyrrolopyridinyl),aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹— (particularly whereinaryl represents phenyl and heteroaryl represents thiadiazolyl, pyrazolylor isoxazolyl), heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—(particularly wherein aryl represents phenyl), heteroaryl-O—Y¹—, C₁₋₆alkyl-SO₂—Y¹— (particularly wherein C₁₋₆ alkyl represents ethyl, propyl,—CH(CH₃)₂ or —C(CH₃)₃), M-Y¹—, J¹-Y¹—, J¹—CO—Y¹—, aryl-SO₂—Y¹—, C₁₋₆alkyl-G-Y¹— (particularly wherein C₁₋₆ alkyl represents methyl and Grepresents —NR¹⁸CO—, —CONR¹⁸—, —NR¹⁸SO₂— or —SO₂NR¹⁸—),heteroaryl-G-aryl-Y¹— (particularly wherein aryl represents phenyl andheteroaryl represents thiazolyl and G represents —NR¹⁸SO₂—), J¹—SO₂—Y¹—(particularly wherein J¹ represents 1-pyrrolidinyl), R¹⁷O(CO)—C₂₋₆alkenyl-Y¹—, R¹⁷NHCO—Y¹— (particularly wherein R¹⁷ represents hydrogen),C₂₋₆ alkynyl-Y¹— (particularly —C≡CH or wherein said C₂₋₆ alkynyl issubstituted with a —OR¹⁷ group, eg. HOCH₂—C≡C—), aryl-CO—Y¹—(particularly wherein aryl represents phenyl), C₃₋₈ cycloalkyl-Y¹— orC₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenyl may beoptionally substituted by one or more hydroxyl or C₁₋₆ alkyl groups andwhich C₂₋₆ alkynyl-Y¹— may be optionally substituted with a —OR¹⁷ group.

[0067] More preferred R¹ groups include C₁ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—,aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—,heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹—, J¹-Y¹—, J¹—CO—Y¹— or C₃₋₈cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl orcycloalkenyl may be optionally substituted by one or more hydroxyl orC₁₋₆ alkyl groups.

[0068] Yet more preferably, R¹ represents aryl-Y¹—, heteroaryl-Y¹,aryl-(O)_(t)-aryl-Y¹—, C₃₋₈ cycloalkyl-Y¹—, C₂₋₆ alkenyl-Y¹— or C₁₋₆alkyl-SO₂—Y¹— especially wherein aryl represents phenyl or naphthyloptionally substituted by one or more C₁₋₆ alkyl (especially methyl),halogen (especially chlorine, fluorine and bromine), CH₃O—, CH₃S—,F₂CHO—, CH₃OC(O)—, —CN, —CF₃, CF₃—S—, CF₃—O—, or (CH₃)₂N—, groups, andwherein heteroaryl represents pyridinyl optionally substituted by one ormore halogen atoms (especially chlorine) and wherein cycloalkylrepresents cyclohexyl. Further preferred substituents of phenyl include—NHCOCH₃ and —CONH₂. Yet further preferred substituents of phenylinclude —SO₂NH₂, —CONHCH₃, —OCH(CH₃)₂, —OC(CH₃)₃, —COOH, —CON(CH₃)₂,—SO₂CH₃, —CONHCH₂CH₃, —CONHcyclopropyl and —SO₂NHcyclopropyl. Alsopreferably, R¹ represents C₂₋₆ alkynyl-Y¹—. A series of particularlypreferred compounds are those wherein R¹ represents aryl-Y¹— whereinaryl represents phenyl optionally substituted by one or more C₁₋₆ alkyl(especially methyl), halogen (especially chlorine, fluorine andbromine), CH₃O—, CH₃S—, F₂CHO—, CH₃OC(O)—, —CN or —CF₃ groups. Furthermost preferred substituents of phenyl include —NHCOCH₃ and —CONH₂. A yetfurther most preferred substituent of phenyl includes SO₂NH₂. Mostpreferably, R¹ will also represent C₂₋₆ alkenyl-Y¹— (particularlyCH₂═CH—Y¹—), C₃₋₄ cycloalkyl-Y¹— (particularly cyclohexyl-Y¹—) and C₁₋₆alkyl-SO₂Y¹— (particularly CH₃SO₂—Y¹—). Also most preferably, R¹represents C₂₋₆ alkynyl-Y¹— (particularly HC≡C—Y¹).

[0069] Especially preferred R¹ groups are aryl-Y¹— and heteroaryl-Y¹—,most especially wherein aryl represents phenyl and heteroaryl representsa 6 membered monocyclic heterocyclic aromatic ring (most particularlytetrazolyl) each of which may be optionally substituted as indicatedabove.

[0070] Preferred substituents of heteroaryl include —CH₃, —CONH₂,—CH₂N(CH₃)₂, halogen (particularly chlorine), —OCH₃, —COOCH₃ and —NH₂.

[0071] Most especially preferred compounds are those wherein R¹represents phenyl-Y¹— which phenyl is substituted with a —CONH₂ or—CONHCH₃ group and tetrazolyl-Y¹— which tetrazolyl is substituted with amethyl group.

[0072] Preferably, Y¹ represents a bond or C₁₋₆ alkylene, morepreferably a bond, methylene or ethylene, propylene, —C(CH₃)₂— or—CH(CH₃)—, particularly a bond, methylene or ethylene, most preferably abond or methylene, especially methylene.

[0073] Preferably, Y² represents a bond.

[0074] Preferably, Y³ represents a bond.

[0075] Preferably, R² represents hydrogen, methyl or hydroxypropyl, morepreferably hydrogen or methyl, especially hydrogen.

[0076] Preferably, R³ represents hydrogen or methyl, especiallyhydrogen.

[0077] Also preferably, R¹ and R² together with the nitrogen atom towhich they are attached form a group of formula J² wherein said nitrogenatom substitutes for either X¹ or X².

[0078] Preferably, X represents methylene.

[0079] Preferably, R⁴ and R⁵ independently represent hydrogen or methyl.Most preferably, R⁴ and R⁵ represent hydrogen.

[0080] Preferably, Z represents a bond, CO, CR¹⁰R⁷(CH₂)_(n),CHR⁷(CH₂)_(n)O, CHR⁷(CH₂)₇S, CHR⁷(CH₂)_(n)OCO or CHR⁷(CH₂)_(n)CO.

[0081] More preferably, Z represents CO, CHR⁷(CH₂)_(n), CHR⁷(CH₂)_(n)O,CHR⁷(CH₂)_(n)S, CHR⁷(CH₂)_(n)OCO or CHR⁷(CH₂)_(n)CO, especially CH₂CO,(CH₂)₂, (CH₂)₂S, (CH₂)₂O, (CH₂)₂OCO, (CH₂)₃CO, CO, CHR⁷, particularlyCH₂, CHCH₃ or CH₂CO, most particularly CH₂ or CH₂CO, especially CH₂.

[0082] Preferably, R⁶ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, CN, aryl,heteroaryl or a group of formula —Y²-J³, more preferably R⁶ representsphenyl (optionally substituted with one or more halogen, phenyl or C₂₋₆alkenyl groups), naphthyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, CN or a 5 memberedaromatic heterocyclic ring containing 1 to 3 heteroatoms selected fromO, N or S optionally substituted by halogen or C₁₋₆ alkyl. Especially,R⁶ represents phenyl (optionally substituted with one or more halogen(especially chlorine, fluorine or iodine), phenyl or 3—CH═CH₂ groups),naphthyl, indolinyl, methyl, —CH═CH₂, —CN or thiophenyl optionallysubstituted by halogen (especially chlorine). Most preferred R⁶represents indolinyl (especially indolin-1-yl) or else represents phenylsubstituted by one or more halogen (eg. chlorine or fluorine) groups,particularly dichlorophenyl, 3-chlorophenyl, 5-chlorothiophenyl,4-fluorophenyl and 3,4-difluorophenyl, most particularly dichlorophenyl,especially 3,4-dichlorophenyl.

[0083] Preferably, R⁷ represents hydrogen, methyl, COOC₁₋₆ alkyl orCONR⁸R⁹, more preferably hydrogen, COOC₁₋₆ alkyl or CONR⁸R⁹ mostpreferably hydrogen, COOEt or CONR⁸R⁹, especially hydrogen.

[0084] Preferably, R⁸ and R⁹ represent hydrogen.

[0085] Preferably, R¹⁰ represents hydrogen.

[0086] Preferably, R¹¹ and R¹² independently represent hydrogen ormethyl.

[0087] Preferably, R¹³ and R¹⁴ independently represent hydrogen ormethyl.

[0088] Preferably, R¹⁵ and R¹⁶ independently represent hydrogen ormethyl or R¹⁵ and R¹⁶ together with the nitrogen atom to which they areattached may form a morpholine, piperidine or pyrrolidine ring,especially hydrogen or methyl.

[0089] Preferably, R¹⁷ represents hydrogen.

[0090] Preferably, R¹⁸ represents hydrogen.

[0091] Preferably, R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₄alkyl or C₃₋₆ cycloalkyl, especially hydrogen, cyclopropyl or methyl.Particularly, R¹⁹ and R²⁰ represent hydrogen.

[0092] Preferably, R^(c) represents hydrogen or methyl, particularlyhydrogen.

[0093] Preferably, R^(d) represents hydrogen or methyl, particularlyhydrogen.

[0094] Preferably, a and b both represent 1.

[0095] Preferably, n represents 0, 1 or 2.

[0096] Preferably, p+q equals an integer from 0 to 2, more preferably, pand q independently represent 0 or 1 such that p+q equals an integerfrom 0 to 1.

[0097] Preferably, t represents 0.

[0098] Preferably, W represents pyrrolidinyl or piperidinyl, especiallypyrrolidinyl.

[0099] Preferably, X¹ represents oxygen, nitrogen or NR¹¹.

[0100] Preferably, X² represents CH₂, oxygen, nitrogen or NR¹².

[0101] Preferably, m¹ and m² independently represent an integer from 1to 2, such that m¹+m² is in the range from 3 to 4.

[0102] Preferably, J¹ represents piperidinyl (particularlypiperidin-4-yl) or tetrahydropyranyl (particularly tetrahydropyran-4-yl)optionally substituted by one or two —COOCH₂CH₃, —COOtBu, —CH₃, —COCH₃,—SO₂N(CH₃)₂, —SO₂CH₃, —COPhenyl or 3, 5-dimethylisoxazol-4-ylsulphonylgroups. Also preferably, J¹ represents morpholinyl, thiopyranyl ortetrahydrothienyl which may be optionally substituted as above(particularly dioxidotetrahydrothienyl).

[0103] Preferred substituents for J¹ include —CH₂-aryl (particularlywherein aryl represents phenyl optionally substituted with one or morehalogen atoms, eg. dichlorophenyl), —COcyclopropyl or —Y³—SO₂heteroaryl(particularly wherein heteroaryl represents dimethylisoxazolyl).

[0104] Preferably, J² represents piperidinyl (particularlypiperidin-1-yl), morpholinyl (particularly N-morpholinyl) or piperazinyl(particularly piperazin-1-yl) optionally substituted by one or twophenyl, —COOCH₂CH₃, —N(CH₃)₂, fluorophenyl, —CH₃, —CONH₂, —COCH₃,—CH₂CO—(N-pyrrolidinyl), hydroxy, —CO-(2-furan), benzyl or —CH₂SO₂CH₃.Preferably, J² also represents thiomorpholinyl, pyrrolidinyl orbenzazepinyl optionally substituted in a similar manner.

[0105] Other preferred substituents for J² include halogen (particularlyfluorine), —COOCH₂CH₃, —CO-furoyl, —SO₂CH₃, -pyridinyl-CH₃ or oxogroups.

[0106] Preferably, J³ represents indolinyl, particularly indolin-1-yl.

[0107] Suitable salts of the compounds of formula (I) includephysiologically acceptable salts and salts which may not bephysiologically acceptable but may be useful in the preparation ofcompounds of formula (I) and physiologically acceptable salts thereof.If appropriate, acid addition salts may be derived from inorganic ororganic acids, for example hydrochlorides, hydrobromides, sulphates,phosphates, acetates, benzoates, citrates, succinates, lactates,tartrates, fumarates, maleates, 1-hydroxy-2-naphthoates, palmoates,methanesulphonates, formates or trifluoroacetates. Examples of solvatesinclude hydrates.

[0108] When compounds of formula (I) contain chiral centres, theinvention extends to mixtures of enantiomers (including racemicmixtures) and diastereoisomers as well as to individual enantiomers.Generally it is preferred to use a compound of formula (I) in the formof a single enantiomer.

[0109] The compounds of formula (I) and salts and solvates thereof maybe prepared by the methodology described hereinafter, constituting afurther aspect of this invention.

[0110] A process according to the invention for preparing a compound offormula (I) comprises:

[0111] (a) reacting a compound of formula (II)

[0112]  wherein R¹, R², R³, R⁴, R⁵, X, a and b are as defined above, ora protected derivative thereof, with a compound of formula L¹-Z-R⁶,wherein Z and R′ are as defined above and L¹ represents a suitableleaving group; or

[0113] (b) forming a compound of formula (I) wherein R² representshydrogen which comprises reacting a compound of formula (III)

[0114]  wherein R³, R⁴, R⁵, R⁶, Z. X, a and b are as defined above, or aprotected derivative thereof, with a compound of formula

[0115] R¹-N═C═O, wherein R¹ is as defined above; or

[0116] (c) reacting a compound of formula (IV)

[0117] wherein R³, R⁴, R⁵, R⁶, Z, X, a and b are as defined above or aprotected derivative thereof and L² represents a suitable leaving group,or a protected derivative thereof, with a compound of formula (V)

[0118]  wherein R¹ and R² are as defined above or a protected derivativethereof; or

[0119] (d) reacting a compound of formula (Vi)

[0120]  wherein R¹ and R² are as defined above and L³ represents asuitable leaving group, or a protected derivative thereof, with acompound of formula (111), or a protected derivative thereof; or

[0121] (e) deprotecting a compound of formula (I) which is protected; or

[0122] (e) interconversion of other compounds of formula (1).

[0123] We also provide a further process according to the invention forpreparing a compound of formula (I) which comprises:

[0124] (g) forming a compound of formula (I) wherein R¹ and R² togetherwith the nitrogen atom to which they are attached form a group offormula J² wherein said nitrogen atom substitutes for either X¹ or X²which comprises reacting a compound of formula (IV) or a protectedderivative thereof with a compound of formula J²H, provided that thecompound of formula J²H has a free —NH group; or

[0125] (h) forming a compound of formula (I) wherein Z representsCR¹⁰R⁷(CH₂)_(n), wherein R¹⁰ represents hydrogen, which comprisesreacting a compound of formula (II) or a protected derivative thereofwith a compound of formula R⁷CO(CH₂)_(n)R⁶, followed by reduction of theresultant imine; or

[0126] (i) forming a compound of formula (I) wherein R¹ represents C₁₋₆alkyl-G-Y¹—, wherein G represents —NR¹⁸CO—, which comprises reacting acompound of formula (VII)

[0127] or a protected derivative thereof wherein R², R³ ⁴, R⁵, R⁶, Y¹ X,Z, a and b are as defined above, with a compound of formula C₁₋₄alkyl-NHR¹⁸.

[0128] Process (a) may be performed in the presence of an inert solventeg. N,N-dimethylformamide optionally in the presence of a base such asN,N-diisopropylethylamine at a suitable temperature eg. roomtemperature. Examples of suitable leaving groups (L¹) include halogen,eg. chlorine.

[0129] Process (b) may be performed in the presence of an inert solventeg dichloromethane at a suitable temperature eg. room temperature.

[0130] Processes (c) and (d) may typically be performed in the presenceof a suitable base eg. pyridine at a suitable temperature e.g. 110° C.,wherein leaving groups L² and L³ may represent 4-nitrophenoxy.Alternatively, when L² and L³ represent 4-nitrophenoxy, suitableconditions may involve the use of N,N-diisopropylethylamine as asuitable base and dichloromethane or N,N-dimethylformamide as a suitablesolvent. Alternatively, where L² and L³ are Merrifield resin bound4-thiophenoxy, processes (c) and (d) may be performed with a suitableadditive e.g. N-methylpyrrolidinone in a microwave oven, for example ata power of 600W for 5 min. Other suitable leaving groups includeimidazolyl. Wherein L² or L³ represent imidazolyl, suitable conditionscomprise the use of 1,1′-carbonyldiimidazole in suitable solvents suchas dichloromethane and N,N-dimethylformamide at a suitable temperature,e.g. between 0° C. and 22° C.

[0131] In process (e), examples of protecting groups and the means fortheir removal can be found in T. W. Greene and P. G. M. Wuts ‘ProtectiveGroups in Organic Synthesis’ (J. Wiley and Sons, 3rd Ed. 1999). Suitableamine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g.benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl),which may be removed by hydrolysis or hydrogenolysis as appropriate.Other suitable amine protecting groups include trifluoroacetyl (—COCF₃)which may be removed by base catalysed hydrolysis or a solid phase resinbound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzylgroup (Ellman linker) or a2,6-dimethoxy-4-[2-(polystyrylmethoxy)ethoxy]benzyl group, which may beremoved by acid catalysed hydrolysis, for example with trifluoroaceticacid.

[0132] Process (f) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic aromatic substitution, ester hydrolysis or amide bondformation. Alternative conditions for process (f) includet-butoxycarbonyl group addition or removal and sulphonylation.

[0133] Process (g) may be performed in an identical manner to theconditions described above for processes (c) and (d).

[0134] Process (h) may be performed in the presence of a suitable acid,eg. acetic acid and a suitable reducing agent, eg. sodiumtriacetoxyborohydride in a suitable solvent, eg. dichloromethane at asuitable temperature, eg. room temperature.

[0135] Process (i) may be performed in the presence of a suitablecoupling reagent, eg. 1,1′-carbonyldiimidazole and a suitable solvent,eg. N,N-dimethylformamide at a suitable temperature, eg. roomtemperature.

[0136] Compounds of formula (II) as the R-isomer, wherein R² and R³ bothrepresent hydrogen, X represents methylene, a and b represent 1 and R⁴and R⁵ both represent hydrogen may be prepared according to thefollowing process:

[0137] wherein R¹ is as defined above and P¹ is a suitable protectinggroup, eg. benzyl.

[0138] Compounds of formula (VIII) may be prepared as described inEP0995746.

[0139] Step (i) typically comprises the use of an inert solvent egdichloromethane at a suitable temperature eg. room temperature. Step(ii) typically comprises a simple deprotection reaction, eg. which maycomprise the use of 10% palladium on activated carbon in the presence ofammonium formate and a suitable solvent, eg. ethanol.

[0140] Compounds of formula (II)^(a) as the S-isomer, wherein R¹ is asdefined above, may be prepared by an analogous process.

[0141] Compounds of formula (IV) may be prepared according to thefollowing process:

[0142] wherein R³, R⁴, R⁵, R⁶, X, a, b and Z are as defined above and L²represents a suitable leaving group as defined above eg. 4-nitrophenoxyor Merrifield resin bound 4-thiophenoxy and L⁴ represents a leavinggroup more labile than L² eg. chlorine or 4-nitrophenoxy. When L²represents 4-nitrophenoxy and L⁴ represents chlorine, step (i) may becarried out in a suitable solvent such as dichloromethane in thepresence of a base such as triethylamine at a suitable temperature suchas room temperature. When L² represents Merrifield resin bound4-thiophenoxy and L⁴ represents 4-nitrophenoxy, step (i) may be carriedout in a suitable solvent such as N,N-dimethylformamide at a suitabletemperature such as room temperature. Alternatively L² and L⁴ mayrepresent imidazole, wherein step (i) may be carried out with1,1′-carbonyldiimidazole, in a suitable solvent e.g. a mixture ofdichloromethane and N,N′-dimethylformamide at a suitable temperaturee.g. between 0° C. and 22° C.

[0143] Compounds of formula (III) may be used in protected form, eg.wherein the amine group is protected when R³ represents hydrogen.Suitable protecting groups are among those described above.

[0144] Compounds of formula (III) may be prepared according to thefollowing process:

[0145] wherein R³, R⁴, R⁵, R⁶, X, a, b and Z are as defined above and L¹represents a suitable leaving group eg. chlorine and P² represents asuitable protecting group eg. one mentioned above, such as —COCF₃. Step(i) comprises the use of a suitable solvent eg. N,N-dimethylformamide inthe presence of suitable reagents eg. sodium iodide and potassiumcarbonate at a suitable temperature eg. room temperature. Step (ii)comprises deprotection under conventional conditions appropriate for theprotecting groups. When P² represents —COCF₃, deprotection may beachieved by the use of water and methanol in the presence of potassiumcarbonate at room temperature. Compounds of formula (III) wherein Zrepresents CR¹⁰R⁷(CH₂)_(n) (wherein R¹⁰ represents hydrogen), may alsobe prepared by reductive amination of compounds of formula (XI) in ananalogous manner to that described in process (h) above.

[0146] Compounds of formula (III) wherein R³ represents hydrogen, Xrepresents methylene, a and b represent 1 and R⁴ and R⁵ are bothattached to the morpholine ring at the 5-position may be preparedaccording to the following process:

[0147] wherein R⁶ and Z are as defined above and L¹ represents asuitable leaving group eg. chlorine. Step (i) comprises heating in theabsence of solvent at between 50 and 60° C. Step (ii) comprises heatingwith 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione at 80° C. undernitrogen, followed by stirring with concentrated sulphuric acid at 150°C.

[0148] Compounds of formula (III) wherein R³ represents H may beprepared according to the following process:

[0149] wherein R⁴, R⁵, R⁶, X, a, b and Z are as defined above and L¹represents a suitable leaving group eg. chlorine. Step (i) comprisesheating a compound of formula (XIV; Merrifield Resin) with sodiumcarbonate in a suitable solvent eg. dimethylsulphoxide at a suitabletemperature eg. 150° C. Step (ii) comprises reacting a compound offormula (XV) with a compound of formula (XVI) in the presence of asuitable solvent eg. tetrahydrofuran at a suitable temperature eg. roomtemperature. Step (iii) comprises the use of suitable solvent eg.N,N-dimethylformamide and a suitable base eg. N,N-diisopropylethylamineat a suitable temperature eg. 70° C., followed by deprotection underconventional conditions appropriate for the Merrifield resin protectinggroup eg. acid catalysed hydrolysis.

[0150] Compounds of formula (VII) may be prepared according to thefollowing process:

[0151] wherein R², R³, R⁴, R⁵, R⁶, Y¹, Z, X, a and b are as definedabove, L² represents a suitable leaving group, eg. 4-nitrophenoxy and P³represents a suitable protecting group eg. C₁₋₆ alkyl, preferablyt-butyl.

[0152] Step (i) typically comprises the use of a suitable base, eg.N,N-diisopropylethylamine and a suitable solvent, eg. dichloromethane ata suitable temperature, eg. room temperature.

[0153] Step (ii) typically comprises the use of a suitable acidicreagent, eg. 4M hydrogen chloride in dioxane at a suitable temperature,eg. room temperature.

[0154] Compounds of formula (V), (VI), (VIII), (X), (XI), (XII), (XIV),(XVI) and (XVIII) are either known or may be prepared in accordance withknown procedures.

[0155] Compounds of formula L¹-Z-R⁶, R¹N═C═O, R⁷CO(CH₂)_(n)R⁶, C₁₋₆alkyl-NHR¹⁸, and J²-H are also either known or may be prepared inaccordance with known procedures.

[0156] Compounds of formula (II) may be prepared in accordance withprocesses analogous to those described above for compounds of formula(I), employing standard protecting group chemistry. For example,employing suitable protection for the morpholine NH, such ast-butoxycarbonyl protection.

[0157] Compounds of formula (II), (III), (IV) and (VII) in protected andunprotected forms and salts and solvates thereof also form an aspect ofthe invention.

[0158] Compounds of the invention may be tested for in vitro and in vivobiological activity in accordance with the following assays:

[0159] (a) CCR-3 Binding Assay

[0160] A CCR-3 competition binding SPA (scintillation proximity assay)was used to assess the affinity of novel compounds for CCR-3. Membranesprepared from K562 cells stably expressing CCR-3 (2.51 g/well) weremixed with 0.25 mg/well wheat-germ agglutinin SPA beads (Amersham) andincubated in binding buffer (HEPES 50 mM, CaCl₂ 1 mM, MgCl₂ 5 mM, 0.5%BSA) at 4° C. for 1.5 hr. Following incubation, 20 pM of [¹²⁵I] eotaxin(Amersham) and increasing concentrations of compound (1 pM to 30 μM)were added and incubated in a 96 well plate for 2 hr at 22° C. thencounted on a Microbeta plate counter. The total assay volume was 100 μl.Competition binding data were analysed by fitting the data with a fourparameter logistic equation. Data are presented as the mean pIC₅₀ values(negative logarithm of the concentration of compound which inhibits[¹²⁵I]eotaxin binding by 50%) from at least two experiments.

[0161] (b) Eosinophil Chemotaxis Assay.

[0162] Compounds were evaluated for their inhibitory effect oneosinophil chemotaxis. Eosinophils were purified from human peripheralblood by standard CD16 cell depletion using a Miltenyi cell separationcolumn and a magnetic Super Macs magnet as previously described (Motegi& Kita, 1998; J. Immunology. 161:4340-6). Cells were re-suspended inRPMI 1640/10% FCS solution and incubated with calcein-AM (MolecularProbes) at 37° C. for 30 mins. Following incubation, the eosinophilswere centrifuged at 400 g for 5 min and re-suspended in RPMI/FCS at 2.2million/ml. Cells were then incubated in the presence of increasingconcentration of compounds (1 pM to 30 μM) at 37° C. for 30 mins. Forcontrol responses cells were incubated with RPMI/FCS only. The agonisteotaxin (either a concentration response curve or for the functionalinhibition curves an EC₈₀ concentration) was added to the lower chamberof a 96 well chemotaxis plate (5 μm filter. Receptor Technologies).Eosinophils (50 μl of 2 million/ml cells) were added to the top chamberof the filter plate and incubated at 37° C. for 45 mins. Cells remainingon top of the chemotaxis filter were removed and the number ofeosinophils which had migrated were quantified by reading the plate on afluorescent plate reader. Inhibition curves for the effect of compoundson eosinophil chemotaxis were analysed by fitting the data with a fourparameter logistic equation. Functional pK_(i) values (fpK_(i)) weregenerated using the equation below (Lazareno & Birdsall, 1995. Br. J.Pharmacol 109:1110-9).${{fp}\quad K\quad i} = \frac{{IC}_{50}}{1 + \left\lbrack \frac{\lbrack{Agonist}\rbrack}{{EC}_{50}} \right\rbrack}$

[0163] (c) Guinea-pig Ovalbumin Model

[0164] Inhibition of Eosinophil Infiltration and Hyper-Reactivity in theGuinea Pig

[0165] In a method based on that described by Danahay et al., 1997,ovalbumin sensitised guinea pigs were dosed with mepyramine (30 mg kg⁻¹ip) to protect against anaphylactic bronchospasm. Test compounds,dissolved in 10% DMSO and 90% PEG200, were given by the oral route, 30minutes before ovalbumin challenge (10 minutes breathing of an aerosolgenerated from a 0.5% solution of ovalbumin). Hyper-reactivity of theairways to the thromboxane mimetic U46619, was measured 24 hours afterovalbumin challenge in unrestrained animals using a whole bodyplethysmograph (Buxco Ltd., USA). The guinea pigs were then sacrificedand the lungs lavaged. Total and differential leukocyte counts were thenobtained for the bronchoalveolar lavage fluid and the percentagereduction in eosinophil accumulation determined (Sanjar et al., 1992).Data was presented as the inhibitory effect of the specified doseexpressed as a percentage of the vehicle control response.

[0166] Examples of disease states in which the compounds of theinvention have potentially beneficial anti-inflammatory effects includediseases of the respiratory tract such as bronchitis (including chronicbronchitis), asthma (including allergen-induced asthmatic reactions),chronic obstructive pulmonary disease (COPD) and rhinitis. Anotherdisease of the respiratory tract in which the compounds of the inventionhave potentially beneficial effects is sinusitis. Other relevant diseasestates include diseases of the gastrointestinal tract such as intestinalinflammatory diseases including inflammatory bowel disease (e.g. Crohn'sdisease or ulcerative colitis) and intestinal inflammatory diseasessecondary to radiation exposure or allergen exposure. Furthermore,compounds of the invention may be used to treat nephritis, skin diseasessuch as psoriasis, eczema, allergic dermatitis and hypersensitivityreactions and diseases of the central nervous system which have aninflammatory component eg. Alzheimer's disease, meningitis, multiplesclerosis and AIDS dementia. Compounds of the present invention may alsobe of use in the treatment of nasal polyposis, conjunctivitis orpruritis. Additionally, the compounds of the present invention may be ofuse in the treatment of viral diseases such as HIV.

[0167] Further examples of disease states in which compounds of theinvention have potentially beneficial effects include cardiovascularconditions such as atherosclerosis, peripheral vascular disease andidiopathic hypereosinophilic syndrome. Other diseases for which thecompounds of the present invention may be beneficial are otherhypereosinophilic diseases such as Churg-strauss syndrome. Additionally,eosinophilia is commonly found in parasitic diseases, especiallyhelminth infections, and thus the compounds of the present invention maybe useful in treating inflammation arising from hyper-eosinophilicstates of diseases such as hydatid cyst (Echinococcus sp.), tapeworminfections (Taenia sp.), blood flukes (schistosomiasis), and nematode(round worms) infections such as:— Hookworm (Ancylostoma sp.), Ascaris,Strongyloides, Trichinella, and particularly lymphatic filariasisincluding Onchocerca, Brugia, Wucheria (Elephantiasis).

[0168] Compounds of the invention may be useful as immunosuppressiveagents and so have use in the treatment of auto-immune diseases such asallograft tissue rejection after transplantation, rheumatoid arthritisand diabetes.

[0169] Compounds of the invention may also be useful in inhibitingmetastasis.

[0170] Diseases of principal interest include asthma, COPD andinflammatory diseases of the upper respiratory tract involving seasonaland perennial rhinitis. Preferred diseases of principle interest includeasthma and inflammatory diseases of the upper respiratory tractinvolving seasonal and perennial rhinitis. Further diseases also ofprinciple interest include inflammatory diseases of the gastrointestinaltract such as inflammatory bowel disease.

[0171] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylaxis as well as the treatment ofestablished conditions. As mentioned above, compounds of formula (I) areuseful as pharmaceuticals, in particular as anti-inflammatory agents.

[0172] There is thus provided as a further aspect of the invention acompound of formula (I) or a physiologically acceptable salt or solvatethereof for use as pharmaceuticals, particularly in the treatment ofpatients with inflammatory conditions, eg. asthma or rhinitis.

[0173] According to another aspect of the invention, there is providedthe use of a compound of formula (I) or a physiologically acceptablesalt or solvate thereof for the manufacture of a medicament for thetreatment of patients with inflammatory conditions, eg. asthma orrhinitis.

[0174] In a further or alternative aspect there is provided a method forthe treatment of a human or animal subject with an inflammatorycondition eg. asthma or rhinitis, which method comprises administeringto said human or animal subject an effective amount of a compound offormula (I) or a physiologically acceptable salt or solvate thereof.

[0175] The compounds according to the invention may be formulated foradministration in any convenient way, and the invention therefore alsoincludes within its scope pharmaceutical compositions for use inanti-inflammatory therapy, comprising a compound of formula (I) or aphysiologically acceptable salt or solvate thereof together, ifdesirable, with one or more physiologically acceptable diluents orcarriers.

[0176] There is also provided a process for preparing such apharmaceutical formulation which comprises mixing the ingredients.

[0177] The compounds according to the invention may, for example, beformulated for oral, inhaled, intranasal, buccal, parenteral or rectaladministration, preferably for oral administration.

[0178] Tablets and capsules for oral administration may containconventional excipients such as binding agents, for example syrup,acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose orpolyvinyl pyrrolidone; fillers, for example, lactose, microcrystallinecellulose, sugar, maize-starch, calcium phosphate or sorbitol;lubricants, for example, magnesium stearate, stearic acid, talc,polyethylene glycol or silica; disintegrants, for example, potatostarch, croscarmellose sodium or sodium starch glycollate; or wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in the art. Oral liquid preparations maybe in the form of, for example, aqueous or oily suspensions, solutions,emulsions, syrups or elixirs, or may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example, sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats;emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; or preservatives, for example, methyl or propylp-hydroxybenzoates or sorbic acid. The preparations may also containbuffer salts, flavouring, colouring and/or sweetening agents (e.g.mannitol) as appropriate.

[0179] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0180] The compounds may also be formulated as suppositories, e.g.containing conventional suppository bases such as cocoa butter or otherglycerides.

[0181] The compounds according to the invention may also be formulatedfor parenteral administration by bolus injection or continuous infusionand may be presented in unit dose form, for instance as ampoules, vials,small volume infusions or pre-filled syringes, or in multi-dosecontainers with an added preservative. The compositions may take suchforms as solutions, suspensions, or emulsions in aqueous or non-aqueousvehicles, and may contain formulatory agents such as anti-oxidants,buffers, antimicrobial agents and/or tonicity adjusting agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water,before use. The dry solid presentation may be prepared by filling asterile powder aseptically into individual sterile containers or byfilling a sterile solution aseptically into each container andfreeze-drying.

[0182] The pharmaceutical compositions according to the invention mayalso be used in combination with other therapeutic agents, for exampleanti-inflammatory agents (such as corticosteroids (e.g. fluticasonepropionate, beclomethasone dipropionate, mometasone furoate,triamcinolone acetonide or budesonide) or NSAIDs (eg. sodiumcromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotrieneantagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2integrin antagonists and adenosine 2a agonists)) or beta adrenergicagents (such as salmeterol, salbutamol, formoterol, fenoterol orterbutaline and salts thereof), anti-histamines (eg methapyrilene orloratadine) or antiinfective agents (eg. antibiotics, antivirals).

[0183] It will be appreciated that when the compounds of the presentinvention are administered in combination with other therapeutic agentsnormally administered by the inhaled or intranasal route, that theresultant pharmaceutical composition may be administered by the inhaledor intranasal route.

[0184] Compounds of the invention may conveniently be administered inamounts of, for example, 0.001 to 500 mg/kg body weight, preferably 0.01to 500 mg/kg body weight, more preferably 0.01 to 100 mg/kg body weight,1 to 4 times daily. The precise dose will of course depend on the ageand condition of the patient and the particular route of administrationchosen.

[0185] The compounds of the invention have the advantage that they maybe more efficacious, show greater selectivity, have fewer side effects,have a longer duration of action, be more bioavailable when administeredby the oral route, have more ready and economic synthesis, or have othermore desirable properties than similar known compounds.

[0186] The invention may be illustrated by reference to the followingexamples:

EXAMPLES

[0187] General Experimental Details

[0188] Standard Automated Preparative HPLC Column, Conditions and Eluent

[0189] Automated preparative high performance liquid chromatography(autoprep. HPLC) was carried out using a Supelco+5 μm (100 mm×22 mminternal diameter) column eluted with a mixture of solvents consistingof (i) 0.1% trifluoroacetic acid in water and (ii) 0.1% trifluoroaceticacid in acetonitrile, the eluent being expressed as the percentage of(ii) in the solvent mixture, at a flow rate of 4 ml per minute.

[0190] Mass Directed Automated Preparative HPLC Column, Conditions andEluent

[0191] Mass directed automated preparative high performance liquidchromatography was carried out using an LCABZ+5 μm (5 cm×10 mm internaldiameter) column, employing gradient elution using two solvent systems,(A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formicacid in water, at a flow rate of 8 ml min⁻¹. Mass spectrometry wascarried out using a VG Platform Mass Spectrometer, with an HP1100 DiodeArray Detector and Accurate Flow Splitter.

[0192] LC/MS System

[0193] Three alternative Liquid Chromatography Mass Spectroscopy (LC/MS)Systems were used:

[0194] System A

[0195] This system used an 3 μm ABZ+PLUS (3.3 cm×4.6 mm internaldiameter) column, eluting with solvents:A—0.1% v/v formic acid+0.077%w/v ammonium acetate in water; and B—95:5 acetonitrile:water+0.05% v/vformic acid, at a flow rate of 3 ml per minute. The following gradientprotocol was used: 100% A for 0.7 mins; A+B mixtures, gradient profile0-100% B over 3.5 mins; hold at 100% B for 1.1 mins; return to 100% Aover 0.2 mins.

[0196] System B

[0197] This system used an 3 μm ABZ+PLUS (3.3 cm×4.6 mm internaldiameter) column, eluting with solvents:A—0.1% v/v formic acid+0.077%w/v ammonium acetate in water; and B—95:5 acetonitrile:water+0.05% v/vformic acid, at a flow rate of 1 ml per minute. The following gradientprotocol was used: 100% A for 1.0 min; A+B mixtures, gradient profile0-100% B over 9.0 mins; hold at 100% B for 3.0 mins; return to 100% Aover 2.0 mins.

[0198] System C

[0199] This system used an 3 μm ABZ+PLUS (3.3 cm×4.6 mm internaldiameter) column, eluting with solvents:A—0.1% v/v formic acid+0.077%w/v ammonium acetate in water; and B—95:5 acetonitrile:water+0.05% v/vformic acid, at a flow rate of 1 ml per minute. The following gradientprotocol was used: 100% A for 2.0 mins; A+B mixtures, gradient profile0-100% B over 20 mins; hold at 100% B for 5.0 mins; return to 100% Aover 2.0 mins; hold at 100% A for 1.0 mins.

[0200] All LC/MS systems used a micromass spectrometer, withelectrospray ionisation mode, positive and negative ion switching, massrange 80-1000 a.m.u.

[0201] Thermospray Mass Spectra

[0202] Thermospray Mass Spectra were determined on a HP 5989A enginemass spectrometer, +ve thermospray, source temperature 250° C., probetemperatures 120° C. (stem), 190° C. (tip), detection mass range 100-850a.m.u. Compounds were injected in 10 μl of a mixture of solventscomprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at aflow rate of 0.7 ml/min.

[0203] Normal Phase Automated Preparative HPLC Column—Conditions

[0204] Normal phase automated preparative high performance liquidchromatography (normal phase autoprep HPLC) was carried out using aNucleosil silica 5 μm (100 mm×20 mm internal diameter) column elutedwith an ethyl acetate:heptane two-step gradient (i) 0% to 25% ethylacetate over 7 min followed by (ii) 25% to 100% ethyl acetate over 5.5min; at a flow rate of 30 ml/min.

[0205] Normal Phase Analytical HPLC Method

[0206] Normal phase automated analytical high performance liquidchromatography (normal phase analytical HPLC) was carried out using aNucleosil silica 3 μm (150 mm×4.6 mm internal diameter) column elutedwith an ethyl acetate:heptane two-step gradient (i) 0% to 40% ethylacetate over 7 min followed by (ii) 40% to 100% ethyl acetate over 2.5min; at a flow rate of 2 ml/min.

[0207] Standard Chiral Analytical HPLC System

[0208] This system used a 250×4.6 mm Chiralpak AD 10 μm column, elutingwith absolute ethanol:heptane mixtures at a flow rate of 1 ml perminute, with UV detection at 215 nm.

[0209] Standard Chiral Preparative HPLC System

[0210] This system used a Chiralpak AD column (2 cm×25 cm), eluting withabsolute ethanol:heptane mixtures (15 ml/min over 25 mins, UV detectionat 215 nm).

[0211] Solid Phase Extraction (Ion Exchange)

[0212] ‘SCX’ refers to Isolute Flash SCX-2 sulphonic acid solid phaseextraction cartridges.

[0213] Organic/Aqueous Phase Separation with Hydrophobic Frits

[0214] ‘Hydrophobic frit’ refers to a Whatman polypropylene filter tubefitted with a PTFE frit, pore size 5.0 μm.

[0215] All temperatures are in ° C.

[0216] Intermediates

[0217] Intermediate 1: 2,2,2-Trifluoro-N-(morpholin-2-ylmethyl)Acetamide

[0218] To a stirred solution of morpholin-2-ylmethylamine (3.1 g) inmethanol (70 ml) under nitrogen was added an-ethereal solution ofethyl-α,α,α-trifluoroacetate (5 ml in 20 ml ether) which had been washedwith saturated aqueous sodium bicarbonate, water and brine, and dried.The mixture was stirred for 30 min at 22° C. before removal of allvolatilesin vacuo. The residue was dissolved in methanol (10 ml) and thevolatiles again removed in vacuo to give the title compound as a whitecrunchy foam (4.9 g).

[0219] Thermospray Mass Spectrum m/z 213 [MH⁺].

[0220] Intermediate 2:N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2,2,2-trifluoroacetamide

[0221] To a stirred solution of Intermediate 1 (3.3 g) inN,N-dimethylformamide (50 ml) under nitrogen was added potassiumcarbonate (2.46 g) and sodium iodide (2.12 g). A solution of3,4-dichlorobenzyl chloride (2 ml) in N,N-dimethylformamide (10 ml) wasadded dropwise to the mixture. The mixture was stirred at 22° C. for 18h before the volatiles were removed in vacuo. The residue waspartitioned between dichloromethane (100 ml) and saturated aqueoussodium carbonate solution (50 ml). The organic phase was subsequentlywashed with additional saturated aqueous sodium carbonate solution (2×50ml) and water (50 ml) before drying over magnesium sulphate, filteringand evaporation of the solventin vacuo to give a pale yellow oil. Theoil was purified by Biotage flash chromatography on a 90 g silicacartridge eluting with 25% ethyl acetate in cyclohexane, to give thetitle compound as a colourless oil (2.97 g).

[0222] LC/MS (System A) R, 2.63 min, Mass Spectrum m/z 371 [MH⁺].

[0223] Intermediate 3: [4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine

[0224] To a stirred solution of Intermediate 2 (2.97 g) in methanol (15ml) and water (5 ml) was added potassium carbonate (5.53 g). The mixturewas stirred at 22° C. for 18 h before the methanol was removed in vacuo.Water (25 ml) was added and the mixture extracted with ethyl acetate(3×30 ml). The combined organic phases were washed with water (5 ml) andsaturated aqueous sodium chloride solution (10 ml) before drying oversodium sulphate, filtering and evaporation of the solvent in vacuo togive a pale yellow oil. The oil was purified by Biotage flashchromatography on a 90 g silica cartridge eluting with 75:8:1dichloromethane/ethanol/0.880 ammonia solution. The required fractionswere combined and the solvent evaporated in vacuo to give the titlecompound as a colourless oil (1.85 g).

[0225] LC/MS (System A) R, 1.77 min, Mass Spectrum m/z 275 [MH⁺].

[0226] Intermediate 3: [4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine(Alternative Synthesis)

[0227] A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (Chem Abs No.40172-06-3, 0.980 g) and2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10 g) was heated at80° C. under nitrogen for 3 h. The resulting solid mass was treated withconcentrated sulphuric acid (1.5 ml) then stirred at 150° C. for 24 h.The mixture was treated with water (100 ml) then washed with ethylacetate (2×100 ml). The dark aqueous phase was basified to ˜pH 12 using5M aqueous sodium hydroxide, then extracted with ethyl acetate (2×100ml). The combined organic extracts were washed with water and brine,dried (Na₂SO₄) and concentrated under vacuum to give the title compoundas a brown oil (1.02 g).

[0228] LC-MS (System A): Rt 1.6 min.

[0229] Intermediate 3A:[4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methylamine Salt withparatoluenesulphonic acid 1:1

[0230] A solution of 2-[(3,4-dichlorobenzyl)amino]ethanol (2.25 g) and2-chloroacrylonitrile (1.0 ml) in tetrahydrofuran (3 ml) was heated at40° C. for 66 h. The solvent was evaporated in vacuo to leave a gum. Theresidue was redissolved in tetrahydrofuran (20 ml) and cooled to 0-5° C.Potassium tert-butoxide (1.2 g) was added portionwise to this solutionover 10 min and the mixture was stirred at 0-5° C. for a further 45 min.The mixture was diluted with water (20 ml) and ethyl acetate (20 ml),the phases were separated and the organic phase was washed with 20% w/waqueous sodium chloride solution. The organic phase was dried oversodium sulfate and the solvent was evaporated in vacuo to leave a gum(2.75 g).

[0231] A portion of this gum (0.22 g) in tetrahydrofuran (1 ml) wastreated dropwise with a 1 M solution of borane.tetrahydrofuran complexin tetrahydrofuran (2.44 ml) at 15-25° C. The mixture was stirred at15-25° C. for 16 h, and methanol (3 ml) was added dropwise. The mixturewas stirred for a further 5 h and the solvent was evaporated in vacuo.The residue was redissolved in ethyl acetate (4 ml) andp-toluenesulfonic acid monohydrate (0.123 g) was added. The mixture washeated at 50° C. for 20 min, and the suspension was cooled to 15-25° C.and stirred for 15 min. The mixture was filtered, washed with ethylacetate and dried to give the title compound (0.123 g) as a white solid.

[0232] LC/MS (System A) R, 1.75 min. Mass spectrum m/z 275/277 [MH⁺]

[0233] Intermediate 4: Benzyl2-{[(trifluoroacetyl)amino]methyl}morpholine-4-carboxylate

[0234] To a stirred solution of Intermediate 1 (6.37 g) in methanol (250ml) under nitrogen was added benzylchloroformate (4.7 ml) andtriethylamine (6.3 ml). The mixture was stirred at 22° C. for 1 h beforethe volatiles were removed in vacuo. The residue was purified by Biotageflash chromatography on a 90 g silica cartridge eluting with 33% ethylacetate in cyclohexane, to give the title compound as a white solid (4.4g).

[0235] LC/MS (System A) R_(t) 3.22 min, Mass Spectrum m/z 347 [MH⁺].

[0236] Intermediate 5: Benzyl 2-(aminomethyl)morpholine-4-carboxylate

[0237] To a stirred solution of Intermediate 4 (4.4 g) in 1:1methanol/water (300 ml) was added potassium carbonate (17.5 g). Themixture was stirred at 22° C. for 36 h before the volatiles wereevaporated in vacuo. The residue was dissolved in water and the solutionextracted with dichloromethane (×3). The combined organic extracts werewashed with saturated aqueous sodium chloride solution, dried overmagnesium sulphate and filtered before evaporation of the solvent invacuo. The residue was dissolved in methanol and purified by solid phaseextraction (Isolute SCX sulphonic acid column), initially washing thecartridge with methanol before eluting with 10% 0.880 ammonia solutionin methanol to give the title compound as a colourless oil (2.27 g).

[0238] LC/MS (System A) R_(t) 2.07 min, Mass Spectrum m/z 251 [MH⁺].

[0239] Intermediate 6: Benzyl2-[({[(4-chlorophenyl)amino]carbonyl}amino)methyl]morpholine-4-carboxylate

[0240] To a stirred solution of Intermediate 5 (2.0 g) indichloromethane (100 ml) was added 4-chlorophenylisocyanate (1.35 g).The mixture was stirred at 22° C. for 18 h before 10% 0.880 ammoniasolution in methanol (10 ml) was added. Stirring was continued for afurther 30 min before the solvent was removed in vacuo. The residue waspurified by Biotage flash chromatography on silica gel, eluting with 33%ethyl acetate/cyclohexane; further purification by Biotage flashchromatography on silica gel, eluting with 500:8:1dichloromethane/ethanol/0.880 ammonia solution gave the impure titlecompound as a buff solid (3.6 g).

[0241] LC/MS (System A) R_(t) 3.41 min, Mass Spectrum m/z 404 [MH⁺].

[0242] Intermediate 7: N-(Morpholin-2-ylmethyl)-N′-phenylurea

[0243] A suspension of 10% palladium on carbon (1.5 g) and Intermediate6 (3.2 g) in ethyl acetate (250 ml) was stirred vigorously underhydrogen at 1 atmosphere and 22° C. for 20 h. The catalyst was filteredoff and the volatiles were removed in vacuo. The procedure was repeatedwith a further portion of the catalyst (1 g) for a further 24 h beforefiltration and solvent evaporation in vacuo. Purification of the residueby Biotage flash chromatography on a 90 g silica cartridge, eluting with100:8:1 dichloromethane/ethanol/0.880 ammonia solution, gave the titlecompound as a colourless oil (1.6 g). LC/MS (System A) R_(t) 1.39 min,Mass Spectrum m/z 236 [MH⁺].

[0244] Intermediate 8: tert-Butyl2-[({[(4-chlorophenyl)amino]carbonyl}amino)methyl]morpholine-4-carboxylate

[0245] To a stirred solution of tert-butyl2-(aminomethyl)morpholine-4-carboxylate (Prepared as described in EP 0468231, 2.4 g) in dichloromethane (100 ml) was added4-chlorophenylisocyanate (1.87 g). The mixture was stirred at 22° C. for16 h before 10% 0.880 ammonia solution in methanol was added. Stirringwas continued for a further 30 min before the solvent was removed invacuo to give the title compound as a white foam (3.98 g).

[0246] LC/MS (System A) R_(t) 3.19 min, Mass Spectrum m/z 370 [MH⁺].

[0247] Intermediate 9: N-(4-Chlorophenyl)-N′-(morpholin-2-ylmethyl)Urea

[0248] Intermediate 8 (1.9 g) was stirred in 4.0M hydrogen chloride in1,4-dioxane (40 ml) at 22° C. for 30 min. The solvent was removed invacuo and the residue was purified by solid phase extraction (IsoluteSCX sulphonic acid column), eluting with methanol followed by 10% 0.880NH₃ solution in methanol, to give the title compound as a cream foam(1.15 g). LC/MS (System A) R_(t) 2.03 min, Mass Spectrum m/z 270 [MH⁺].

[0249] Intermediate 10: 4-Nitrophenyl[4-(3,4-dichlorobenzyl)morpholin-2-yl]methylcarbamate

[0250] Triethylamine (0.09 ml) was added to solution of Intermediate 3(0.150 g, 0.545 mmol) in dichloromethane (3 ml) with stirring at 20° C.under nitrogen. The solution was cooled to 0° C. and a solution of4-nitrophenyl chloroformate (0.121 g) in dichloromethane (1 ml) wasadded drop-wise. The resultant mixture was stirred for 4 h at 0° C. Thesolution was allowed to warm to 20° C., washed with brine (4 ml), dried(MgSO₄), and concentrated in vacuo. Purification by Biotage flashchromatography on silica gel, eluting with 35% ethyl acetate incyclohexane, gave the title compound as a pale yellow solid (0.119 g).LC/MS (system A) R_(t) 3.01 min, Mass Spectrum m/z 441 [MH⁺].

[0251] Intermediate 11:1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine

[0252] Intermediate 3 (racemic mixture, 8 g) was separated into itssingle enantiomers by preparative chiral-HPLC. The separation wascarried out using a 2″×22 cm Chiralpak AD 20 μm column, Merck self packDAC system, eluting with 95:5:0.1 (v/v) heptane: absolute ethanol:diethylamine (flow rate: 55 ml/min over 40 min, UV detection 225 nm);sample load preparation: 400 mg sample in 20 ml 3:2 (v/v) absoluteethanol: system eluent. The title compound (2.49 g) was obtained asfollows: preparative HPLC retention time 23.0 min.

[0253] Intermediate 11A:1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine Salt withD-tartaric Acid 1:1

[0254] 35% Hydrazine in water (1.8 ml) was added to a slurry ofIntermediate 42 (5 g) in industrial methylated spirits (75 ml), and themixture was heated to reflux. Chloroform (75 ml) was added and themixture was heated under reflux for 65 h. The reaction mixture wascooled to 0-4° C. and allowed to stand for 15 min. The by-productphthalhydrazide was removed by vacuum filtration and washed withchloroform (50 ml). The filtrate was washed with water (50 ml, 25 ml),dried (MgSO₄), and the solvent evaporated in vacuo to give an oil. Thiswas dissolved in methanol (20 ml), which was evaporated in vacuo to givean oil. The oil was dissolved in methanol (100 ml) and D-tartaric acid(1.05 g) was added. The mixture was heated to and maintained at refluxfor 30 min. The solution was cooled to 45-50° C., then seeded. Theslurry was held at this temperature for 30 min, then cooled to 0-4° C.and allowed to stand for 30 min. The product was isolated by filtrationto give the title compound as a white solid (2.59 g).

[0255] A sample of the crude D-tartrate salt (500 mg) was dissolved inwater (1.4 ml). Methanol (23 ml) was added to give a slurry which washeated to reflux to give a solution. The mixture was stirred at refluxfor 30 min, then cooled slowly, seeding at 55° C. The resultant slurrywas cooled to 0-4° C. and allowed to stand 30 min. The product wasisolated by filtration to give the title compound as a white solid(0.355 g).

[0256] ee: 91.6% ee

[0257] LC/MS (System A) R. 1.75 min. Mass spectrum m/z 275/277 [MH⁺]

[0258] Chiral analytical HPLC (Chiralpak AD column, 4.6×250 mm,eluent50:50:0.1 MeOH: EtOH: Butylamine, flow rate 0.5 ml/min, UVdetection at 220 nm), R_(t) 8.9 min.

[0259] Intermediate 11A (Alternative Procedure):1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methanamine Salt withD-tartaric Acid 1:1

[0260] Intermediate 3 (0.613 g) was dissolved in methanol (12.3 ml).D-Tartaric acid (0.335 g) was added and the slurry was heated to refluxfor 50 min. The mixture was allowed to cool to 0-5° C. and theprecipitate isolated by filtration to give the title compound as a whitesolid (0.4 g).

[0261] ee: 76% ee

[0262] Chiral analytical HPLC (Chiralpak AD column, 4.6×250 mm,eluent50:50:0.1 MeOH: EtOH: Butylamine, flow rate 0.5 ml/min, UVdetection at 220 nm), R_(t) 8.9 min.

[0263] Intermediate 12:1-[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine

[0264] Intermediate 12 was prepared in an analogous manner toIntermediate 11 yielding the title compound (2.24 g) as follows:preparative HPLC retention time 27.8 min.

[0265] Intermediate 12A:1-[(2R)₄-(3,4-Dichlorobenzyl)morpholin-2-yl]Methanamine Salt withL-tartaric Acid 1:1

[0266] Intermediate 3 (0.500 g) was dissolved in methanol (5 ml).L-Tartaric acid (0.273 g) was added and the mixture was heated to −65°C. to give a milky slurry, and maintained at this temperature for 1 h.Further methanol (5 ml) was added and the mixture left to cool slowly to15-25° C., then cooled further to 04° C. The mixture was stirred for 30min at this temperature and the product isolated by filtration to givethe title compound as a white solid (0.38 g).

[0267] ee: 78%

[0268] LC/MS (System A) R_(t) 1.75 min. Mass spectrum m/z 275/277 [MH⁺]

[0269] Chiral analytical HPLC (Chiralpak AD column, 4.6×250 mm, eluent50:50:0.1 MeOH: EtOH: Butylamine, flow rate 0.5 ml/min, UV detection at220 nm), R_(t) 10.5 min.

[0270] Intermediate 13: 4-Nitrophenyl[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methylcarbamate

[0271] Intermediate 13 was prepared in an analogous manner toIntermediate 10 from Intermediate 11 (0.225 g) and4-nitrophenylchloroformate (0.182 g) to yield the title compound(0.2 g).

[0272] LC-MS (System A) R_(t) 3.1 mins. Mass Spectrum m/z 441 [MH⁺].

[0273] Intermediate 14: 4-Nitrophenyl[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methylcarbamate

[0274] Intermediate 14 was prepared in an analogous manner toIntermediate 10 from Intermediate 12 (0.21 g) and4-nitrophenylchloroformate (0.17 g) to yield the title compound(0.23 g).

[0275] LC-MS (System A) R_(t) 3.09 mins. Mass Spectrum m/z 441 [MH⁺].

[0276] Intermediate 15: tert-Butyl4-{[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}piperidine-1-carboxylate

[0277] Intermediate 15 was prepared in an analogous manner to Example 43using tetrahydrofuran as solvent, without base, to give the titlecompound as a white solid (0.157 g).

[0278] LC/MS (System A) R_(t) 2.92 min, Mass spectrum m/z 501 [MH⁺].

[0279] Intermediate 16:N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-piperidin-4-ylureaHydrochloride

[0280] Intermediate 15 (0.157 g) was stirred in dioxane (4 ml)containing 4.0M hydrogen chloride in dioxane (0.78 ml) for 16 h, at 23°C. under nitrogen. The solvent was removed in vacuo, azeotroped withdichloromethane (20 ml), triturated in ether and dried under vacuum togive the title compound as a pale yellow solid (0.12 g).

[0281] LC/MS (System A) R_(t) 2.02 min, Mass spectrum m/z 401 [MH⁺].

[0282] Intermediate 17 tert-butyl4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}methyl)piperidine-1-carboxylate

[0283] Intermediate 17 was made in an analogous manner to that ofExample 57

[0284] LC-MS (System A) R_(t) 2.72 mins Mass Spectrum m/z 515-[MH⁺].

[0285] Intermediate 18:N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N′-(piperidin-4-ylmethyl)UreaDihydrochloride

[0286] Intermediate 17 (0.390 g) was stirred in 4.0M hydrogen chloridein dioxane (4 ml) for 2 h, at 23° C. under nitrogen. The solvent wasremoved in vacuo, azeotroped with dichloromethane (20 ml), and driedunder vacuum to give the title compound as a pale yellow solid, (0.33g).

[0287] LC/MS (System A) R_(t) 1.84 min, Mass spectrum m/z 415 [MH⁺].

[0288] Intermediate 19[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methylamine

[0289] Intermediate 19 was made in an analogous manner to that ofIntermediate 11

[0290] Preparative HPLC retention time 26.1 min

[0291] Intermediate 20[(2S)-4-(2,3-dichlorobenzyl)Morpholin-2-yl]Methylamine

[0292] Intermediate 20 was made in an analogous manner to that ofIntermediate 11

[0293] Preparative HPLC retention time 25.3 min

[0294] Intermediate 21[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methylamine

[0295] Intermediate 21 was made in an analogous manner to that ofIntermediate 11

[0296] Preparative HPLC retention time 28.3 min

[0297] Intermediate 22: 4-Nitrophenyl prop-2-ynylcarbamate

[0298] Propargylamine (0.017 ml) and triethylamine (0.38 ml) indichloromethane (2 ml) were added dropwise to p-nitrophenylchloroformate(0.55 g) in dichloromethane (3 ml) at 0° C. The solution was stirred for1 h at this temperature then at 23° C. for 5 h. The solvent was removedin vacuo and the residue purified by solid phase extraction (10 g silicagel cartridge, Varian Bond Elut), eluting with 20-60% ethyl acetate incyclohexane, to give the title compound as a white solid (0.419 g).

[0299] LC/MS (system A) R_(t) 2.67 min Mass spectrum m/z 220 [MH⁺].

[0300] Intermediate 23:{(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methylamine

[0301] Intermediate 23 was made in an analogous manner to that ofIntermediate 11

[0302] Chiral preparative HPLC retention time 25.2 min

[0303] Intermediate 24:[(2R,5R)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-yl]methylamine(mixture with trans isomer, cis:trans 60:40)

[0304] Intermediate 24 was made in an analogous manner to that ofIntermediate 31 from (2R)-2-aminopropan-1-ol.

[0305] LC-MS (System A): R_(t) 1.9 mins Mass Spectrum m/z 289 [MH⁺].

[0306] Intermediate 25: tert-Butyl4-{[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}Butanoate

[0307] 4-Aminobutyric acid tert-butyl ester hydrochloride (0.235 g) wasadded to a stirred solution of Intermediate 13 (0.440 g) andN,N-diisopropylethylamine (0.42 ml) in dry dichloromethane (20 ml) undernitrogen, and the mixture was stirred at 22° C. for 18 h. The mixturewas treated with saturated aqueous potassium carbonate (20 ml) andstirred for 5 min. The layers were separated and the organic layerapplied to a silica gel cartridge (10 g Varian Bond Elut). Elution withdichloromethane, ether, ethyl acetate, and acetone gave the crudeproduct (0.357 g). Further purification by chromatography on silica gel(10 g Varian Bond Elut cartridge), eluting with dichloromethane (1column volume), ether (4 column volumes) and ethyl acetate (8 columnvolumes) gave the title compound as a gum (0.345 g).

[0308] LC-MS (System A) R_(t) 2.66 min Mass Spectrum m/z 460 [MH⁺].

[0309] Intermediate 26:4-{[({[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}butanoicAcid Hydrochloride

[0310] Intermediate 25 (0.345 g) was dissolved in 4M hydrogen chloridein dioxane (5 ml), and the mixture was allowed to stand at 22° C. for19.5 h. The solvent was evaporated in vacuo to give the title compoundas a white solid (0.330 g).

[0311] LC-MS (System A) R_(t) 2.16 min Mass Spectrum m/z 404 [MH⁺].

[0312] Intermediate 27:2-[3-(pyrrolidin-1-ylsulfonyl)propyl]-1H-isoindole-1,3(2H)-dione

[0313] A solution of3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propane-1-sulfonyl chloride(0.288 g) in dry tetrahydrofuran (5 ml) was treated withN,N-diisopropylethylamine (0.350 ml) and pyrrolidine (0.10 ml) at 22° C.under nitrogen, and the mixture was stirred at 22° C. for 1 h. Afterstanding overnight at room temperature, the mixture was partitionedbetween saturated aqueous sodium bicarbonate (10 ml) and ethyl acetate(2×10 ml). The organic layers were washed with brine, dried (MgSO₄) andevaporated in vacuo to give a white solid (0.145 g).

[0314] LC-MS (System A) R_(t) 2.81 min. Mass Spectrum m/z 323 [MH⁺].

[0315] Intermediate 28: 3-(Pyrrolidin-1-ylsulfonyl)Propylamine

[0316] A solution of Intermediate 27 (0.139 g) in isopropanol (7.6 ml)and water (1.3 ml) was treated with sodium borohydride (0.081 g), andthe mixture was stirred at room temperature under nitrogen for 19 h.Glacial acetic acid (0.45 ml) was added cautiously and the mixtureheated at 80° C. for 2 h. The solvents were evaporated in vacuo to givea white solid, which was dissolved in methanol and applied to asulphonic acid ion exchange cartridge (10 g Isolute SCX). Elution withmethanol followed by 10% 0.880 ammonia in methanol, and evaporation ofthe ammonia/methanol fraction gave the title compound as a white solid(0.027 g).

[0317] TLC SiO₂ (dichloromethane:ethanol:0.880 ammonia 89:10:1) Rf 0.2

[0318] Intermediate 29: 4-Nitrophenyl[(2S)-4-(3,4-dichlorobenzyl)Morpholin-2-yl]methylcarbamate Hydrochloride

[0319] A mixture of triethylamine (0.101 ml) and Intermediate 11 (2.0 g)in dichloromethane (20 ml) was added dropwise to a solution of4-nitrophenyl chloroformate (1.62 g) in dichloromethane (10 ml) withstirring at 0° C. under nitrogen. The solution was stirred for 3 h at 0°C., allowed to warm to 20° C., and stand for 18 h. The volatilecomponents were evaporated in vacuo, and the residue was purified byBiotage flash chromatography on silica gel (90 g cartridge), elutinginitially with 10% methanol in dichloromethane and subsequently with 20%methanol in dichloromethane, to give the title compound as a light brownsolid (2.5 g).

[0320] LCMS (System A) R, 2.89 min Mass Spectrum m/z 441 [MH⁺]

[0321] Intermediate 30: 1-(2-Methyl-2H-tetraazol-5-yl)MethanamineHydrochloride

[0322] To Intermediate 37 (0.47 g) was added 4.0M hydrogen chloride in1,4-dioxane (5 ml). The mixture was stirred at 22° C. for 3 h, and thesolvent removed in vacuo. The residue was again dissolved in 4.0Mhydrogen chloride in 1,4-dioxane (5 ml), and left to stand at 22° C. for18 h. Evaporation of the solvent in vacuo gave the title compound as acream solid (0.319 g). Thermospray Mass Spectrum m/z=114 [MH⁺]

[0323] Intermediate 31:1-[4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]Methanamine (Cis/TransRatio 2:1)

[0324] A mixture of Intermediate 43 (0.470 g) and2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.410 g) was heated at80° C. under nitrogen for 5 h. The mixture was treated with concentratedsulphuric acid (0.6 ml) then stirred at 150° C. for 42 h. The mixturewas treated with water (50 ml) then washed with ethyl acetate (2×50 ml).The dark aqueous phase was basified to ˜pH 11 using 5M aqueous sodiumhydroxide then extracted with ethyl acetate (2×50 ml). The combinedorganic extracts were washed with water and brine, dried (Na₂SO₄) andconcentrated under vacuum to give the title compound as a brown oil(0.42 g).

[0325] LC-MS (System A): R_(t) 1.74 min.

[0326] Intermediate 32: tert-Butyl{(2S)-4-[1-(3,4-dichlorophenyl)ethyl]morpholin-2-yl}methylcarbamate

[0327] tert-Butyl (2R)-morpholin-2-ylmethylcarbamate (2.00 g) inN,N-dimethylformamide (16 ml) was treated with N,N-diisopropylethylamine(1.6 ml) followed by 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g).After stirring for five days at room temperature, further portions of4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g) andN,N-diisopropylethylamine (1.6 ml) were added and stirring continued for24 h at room temperature. The solution was treated with dichloromethane(70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) and themixture shaken vigorously. The organic phase was separated and appliedequally onto sulphonic acid ion exchange cartridges (5×10 g Isolute SCX,pre-treated with methanol). The cartridges were each eluted withmethanol (one column volume) followed by 10% 0.880 ammonia in methanol(one column volume); evaporation in vacuo of the combined basicfractions gave the title compound as a clear colourless gum (3.22 g)

[0328] LC-MS (System A) R_(t) 2.74 min, Mass Spectrum m/z 389 [MH⁺].

[0329] Intermediate 33:1-{(2S)-4-[1-(3,4-Dichlorophenyl)ethyl]morpholin-2-yl}MethanamineDihydrochloride

[0330] Intermediate 32 was treated with 4M hydrogen chloride in dioxane(15 ml) and the solution stirred for 2 h at room temperature. Thesolution was treated with methanol (20 ml) and concentrated in vacuo togive the title compound as an off-white solid (1.53 g).

[0331] LC/MS (System A) R_(t) 1.86 min and 1.91 min, Mass spectrum m/z289 [MH⁺].

[0332] Intermediates 34 and 35: 4-Nitrophenyl{(2S)-4-[1-(3,4-dichlorophenyl)ethyl]morpholin-2-yl}methylcarbamate(Isomer I and II, Respectively)

[0333] Intermediate 33 (0.724 g) in dichloromethane (5 ml) was treatedwith triethylamine (1.14 ml), forming a slurry which was addedportion-wise over 5 min to a solution of 4-nitrophenyl chloroformate(0.444 g) in anhydrous dichloromethane (5 ml) at 0° C. under nitrogen.The stirring solution was allowed to warm to room temperature over 2 h,then filtered; the filtrate was purified directly by chromatography onsilica gel (Biotage 90 g column), eluting with 35-40% ethyl acetate incyclohexane, and appropriate fractions evaporated in vacuo to give thetitle compound (Isomer I) as an opaque yellow film (0.202 g).

[0334] LC/MS (System A) Rt 2.90 min, Mass spectrum m/z 454 [MH⁺].

[0335] Analytical Chiral HPLC R_(t) 18.03 mins (eluent 25%EtOH/heptane).

[0336] Appropriate other fractions were combined and concentrated invacuo to give the other title compound (Isomer II) (0.196 g) as anopaque yellow film.

[0337] LC/MS (System A) R_(t) 2.88 min, Mass spectrum m/z 454 [MH⁺].

[0338] Analytical Chiral HPLC R_(t) 15.38 mins (eluent 25%EtOH/heptane).

[0339] Intermediate 36: tert-Butyl 1H-tetraazol-5-ylmethylcarbamate

[0340] To a stirred solution of 1-(1H-tetraazol-5-yl)methanamine (6.0 g)in water (120 ml) at 22° C. was added sodium hydroxide (4.8 g), followedby dropwise addition of a solution of di-tert-butyldicarbonate (13.48 g)in methanol (20 ml). Further methanol (40 ml) was added to the mixtureand stirring continued for 4 h; the mixture was then allowed to standfor 60 h at 4° C. The methanol was evaporated in vacuo and the aqueousresidue acidified to approximately pH 6 with 2M aqueous hydrochloricacid. The aqueous mixture was extracted with ethyl acetate (×3) and thecombined organic extracts were washed with saturated aqueous sodiumchloride, dried (MgSO₄) and the solvent evaporated in vacuo to give thetitle compound as a white solid (1.50 g).

[0341] Thermospray Mass Spectrum m/z 200 [MH⁺], 217 [MNH₄ ⁺]

[0342] Intermediate 37: tert-Butyl(2-methyl-2H-tetraazol-5-yl)Methylcarbamate

[0343] To a stirred solution of Intermediate 36 (1.0 g) indichloromethane (35 ml) and methanol (10 ml) at 22° C. under nitrogenwas added dropwise 10% trimethylsilyldiazomethane in hexane (12.0 ml).The mixture was stirred for 2 h at 22° C. before acetic acid (2 ml) wasadded dropwise and the solvents were evaporated in vacuo. The cruderesidue was purified by Biotage flash column chromatography on silicagel (90 g cartridge), eluting with 10% cyclohexane in ether. Thefractions for the first eluting isomer were combined and the solventsevaporated in vacuo to give the title compound as pale yellow crystals(0.487 g).

[0344] Thermospray Mass Spectrum m/z=214 [MH⁺]

[0345] TLC (SiO₂), 10% cyclohexane/ether) R_(f)=0.35, visualised withKMnO₄

[0346] Intermediate 38: tert-Butyl 3-(ethylthio)propylcarbamate

[0347] A solution of tert-butyl 3-bromopropylcarbamate (0.30 g) inN,N-dimethylformamide (5 ml) was treated with ethanethiol (0.104 ml) andpotassium carbonate (0.29 g), and the mixture stirred at roomtemperature overnight. The mixture was partitioned between water (20 ml)and dichloromethane (30 ml), and the organic layers evaporated in vacuoto give the title compound (0.236 g).

[0348] TLC SiO₂ (cyclohexane:ethyl acetate 4:1) Rf 0.5.

[0349] Intermediate 39: tert-Butyl 3-(ethylsulfonyl)Propylcarbamate

[0350] 3-Chloroperoxybenzoic acid (0.373 g) was added to a stirredsolution of Intermediate 38 (0.236 g) in dry dichloromethane (6 ml) at22° C. under nitrogen, and the mixture was stirred at 22° C. for 18 h.The mixture was treated with saturated aqueous sodium carbonate (10 ml),stirred for 3 min, and the separated organic layer evaporated in vacuoto give the title compound (0.275 g).

[0351] NMR (CDCl₃) 5.15δ(1H, br.t, NH), 3.25δ(2H, q, CH₂), 3.00δ(H, t+q,2×CH₂), 2.03δ(H, m, CH₂), 1.50-1.30δ(12H, s+t, 4×CH₃)

[0352] Intermediate 40: 3-(Ethylsulfonyl)propan-1-amine Hydrochloride

[0353] Intermediate 39 (0.275 g) was dissolved in 4M hydrogen chloridein dioxane (3 ml), and the solution was allowed to stand at 22° C. for 2h. The solvent was evaporated in vacuo to give the title compound as awhite solid (186 mg).

[0354] NMR (D4 MeOH) 3.25δ(2H, t, CH₂), 3.15δ(4H, t+q, 2×CH₂), 2.18δ(2H,m, CH₂), 1.38δ(3H, t, CH₃).

[0355] Intermediate 41:[4-(3,4-Dichlorobenzyl)-1,4-oxazepan-2-yl]methylamine

[0356] Formyl polystyrene resin (1.6 g, loading=2.95 mmol/g) was washedfive times with tetrahydrofuran in a glass sintered peptide vessel. Asolution of 1-(1,4-oxazepan-2-yl)methanamine (0.619 g) intetrahydrofuran (20 ml) was added and the mixture shaken at 22° C. for18 h. The mixture was filtered and the resin washed with tetrahydrofuran(4×20 ml) and methanol (3×10 ml) and dried. A portion of the dried resin(1.2 g) was suspended in N,N-dimethylformamide (20 ml),N,N-diisopropylethylamine (2.04 ml) and 3,4-dichlorobenzylchloride wereadded. The mixture was stirred gently at 70° C. for 22 h. After cooling,the mixture was filtered and the resin washed with THF (5×10 ml) anddichloromethane (5×10 ml) and air-dried on the sinter. The resin wasplaced into a glass sintered peptide vessel and suspended intetrahydrofuran (9 ml); conc. hydrochloric acid (3 ml) was added, andthe vessel was shaken for 2 h. The resin was filtered off and washedwith tetrahydrofuran (2×10 ml). The combined filtrates were concentratedin vacuo to give a clear oil, which was applied to an ion exchangecartridge (10 g Isolute SCX, pre-conditioned with methanol). Elutionwith methanol (3 column volumes) followed 10% 0.880 ammonia in methanol(2 column volumes) and evaporation of the basic fractions in vacuo gavea residue. The ion exchange purification was repeated (as above) to givethe title compound as a colourless gum (0.256 g).

[0357]¹H NMR (CDCl₃): 7.46δ(H, d, Aromatic CH), 7.38δ(1H, d, AromaticCH), 7.19δ(1H, dd, Aromatic CH), 3.94δ(1H, m, CH), 3.80δ(1H, m, CH),3.59δ(2H, s, CH₂), 3.57δ(1H, m, CH), 2.82-2.53δ(5H, m, 5×CH), 2.38δ(1H,dd, CH), 1.98-1.78δ(2H, m, 2×CH), 1.49δ(2H+H₂O, br.s, NH₂).

[0358] Intermediate 42:2-{[4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}-1H-isoindole-1,3(2H)-dione

[0359] To a solution of 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione(N-(2,3-epoxypropyl)-phthalimide) (2 g) in tetrahydrofuran (4 ml) wasadded 2-[(3,4-dichlorobenzyl)amino]ethanol (2.16 g) with stirring, undera nitrogen atmosphere. The mixture was heated to 66° C. for 22 h, thencooled to 0° C. A further portion of tetrahydrofuran (10 ml) was added,followed by triphenylphosphine (2.88 g). Diisopropyl azodicarboxylate(2.2 g) was then added over 10 min. The mixture was stirred at 0° C. fora further 30 min, and at room temperature for 14 h. To the crudesolution was added ethyl acetate (100 ml), then 2M aqueous hydrochloricacid (250 ml). The resulting white precipitate was isolated byfiltration, and dried in vacuo to give the title compound as its whitecrystalline hydrochoride salt (2.01 g). This was partitioned between 8%aqueous sodium bicarbonate (200 ml) and ethyl acetate (50 ml). Theorganic phase was separated, dried over magnesium sulfate and thesolvent evaporated in vacuo to give a solid. Dichloromethane (20 ml) wasadded to the residue and the solvent again evaporated in vacuo to givethe title compound as a white solid (1.1 g).

[0360] LC/MS R_(f) 2.91 min. Mass Spectrum m/z 405 [MH⁺]

[0361] Intermediate 43: 2-[(3,4 Dichlorobenzyl)Amino]Propan-1-ol

[0362] 3,4-Dichlorobenzyl chloride (0.988 g) was added to2-amino-1-propanol (4.10 g) and the mixture was stirred at 50° C. undernitrogen for 2 h. The mixture was partitioned between saturated aqueoussodium bicarbonate (100 ml) and ethyl acetate (100 ml) and the phaseswere separated. The organic layer was washed with water (4×100 ml) andbrine, dried (Na₂SO₄) then concentrated under vacuum to give the titlecompound as a white solid (0.935 g).

[0363] LC-MS (System A): R_(t) 2.13 min.

EXAMPLES Example 1N-Benzyl-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea

[0364] To a stirred solution of Intermediate 3 (0.025 g) indichloromethane (1 ml) was added benzylisocyanate (16.8 pt). The mixturewas stirred at 22° C. for 18 h before tris-(2-aminoethyl)aminepolystyrene (Argonaut Technologies, 0.04 g@3.85 mmol/g) was added.Stirring was continued for a further 72 h before the mixture was pouredonto a 1 g solid phase extraction (Isolute SCX sulphonic acid)cartridge. The cartridge was washed with methanol before eluting with10% 0.880 ammonia solution in methanol. The basic fraction wasevaporated in vacuo to give a pale yellow solid. The solid was purifiedby eluting through a 1 g silica solid phase extraction cartridge (VarianBondelut) eluting sequentially with dichloromethane, ether, ethylacetate, acetone, acetonitrile and methanol, to give the title compoundas a white solid (0.031 g). LC/MS (System A) R. 2.22 min, Mass Spectrumm/z 408 [MH⁺].

Example 2N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(4-methoxybenzyl)urea

[0365] Example 2 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-(isocyanatomethyl)-4-methoxybenzene (19.5 μl) to give the titlecompound (0.0257 g). LC-MS (System A): Rt 2.23 mins, Mass Spectrum m/z438 [MH⁺].

Example 3N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(4-methylbenzyl)Urea

[0366] Example 3 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-(isocyanatomethyl)-4-methylbenzene (19.1 μl) to give the titlecompound (0.0318 g). LC-MS (System A): Rt 2.33 mins, Mass Spectrum m/z422 [MH⁺].

Example 4N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(3-methylbenzyl)Urea

[0367] Example 4 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-(isocyanatomethyl)-3-methylbenzene (19.111) to give the title compound(0.0382 g). LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 422 [MH⁺].

Example 5 N-(3-Cyanophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}Urea

[0368] Example 5 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 3-isocyanatobenzonitrile(0.0196 g) to give the title compound (0.0257 g). LC-MS (System A):R_(t) 2.29 mins, Mass Spectrum m/z 419 [MH⁺].

Example 6N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(2-methylbenzyl)Urea

[0369] Example 6 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-(isocyanatomethyl)-2-methylbenzene (0.0201 g) to give the titlecompound (0.0269 g). LC-MS (System A): Rt 2.31 mins, Mass Spectrum m/z422 [MH⁺].

Example 7N-Cyclohexyl-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0370] Example 7 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and isocyanatocyclohexane (17.41μl) to give the title compound (0.0298 g). LC-MS (System A): Rt 2.26mins, Mass Spectrum m/z 400 [MH⁺].

Example 8N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(2-phenylethyl)Urea

[0371] Example 8 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and (2-isocyanatoethyl)benzene(18.9 μl) to give the title compound (0.0312 g). LC-MS (System A): Rt2.29 mins, Mass Spectrum m/z 422 [MH⁺].

Example 9N-({4-[2-(2,3-Dihydro-1H-indol-1-yl)-2-oxoethyl]morpholin-2-yl}methyl)-N′-phenylurea

[0372] To a stirred solution of Intermediate 7 (0.01 g) inN,N-dimethylformamide (0.5 ml) was added 1-(2-chloroacetyl)indoline(0.0092 g). The mixture was stirred at 22° C. for 17 h beforetris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.01 g@4.46mmol/g) and polystyrene methyl isocyanate (Argonaut Technologies, 0.033g@1.39 mmol/g) was added. Stirring was continued for a further 30 minbefore the mixture was purified by solid phase extraction (1 g IsoluteSCX sulphonic acid column), eluting with methanol followed by 10% 0.880ammonia solution in methanol. The basic fraction was evaporated in vacuoto give the title compound as a white solid (0.012 g). LC/MS (System A)R, 2.69 min, Mass Spectrum m/z 394 [MH⁺].

Example 10 N-Allyl-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}Urea

[0373] Example 10 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 3-isocyanatoprop-1-ene(12.0,u) to give the title compound (0.027 g). LC-MS (System A): R_(t)1.93 mins, Mass Spectrum m/z 358 [MH⁺].

Example 11N-{[4-(3.4-Dichlorobenzyl)morpholin-2-yl]methyl}-N-(3-fluorophenyl)Urea

[0374] Example 11 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-fluoro-3-isocyanatobenzene(15.6 μl) to give the title compound (0.019 g). LC-MS (System A): Rt2.35 mins, Mass Spectrum m/z 412 [MH⁺].

Example 12N-(3-Bromophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}Urea

[0375] Example 12 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-bromo-3-isocyanatobenzene(17.0 μl) to give the title compound (0.03 g). LC-MS (System A): Rt 2.50mins, Mass Spectrum m/z 472 [MH⁺].

Example 13N-(3-Chlorophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0376] Example 13 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-chloro-3-isocyanatobenzene(16.6 μl) to give the title compound (0.0247 g). LC-MS (System A): Rt2.46 mins, Mass Spectrum m/z 428 [MH⁺].

Example 14N-(4-Chlorophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0377] Example 14 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-chloro-4-isocyanatobenzene(17.4 μl) to give the title compound (0.0275 g). LC-MS (System A): R_(t)2.45 mins, Mass Spectrum m/z 428 [MH⁺].

Example 15 Methyl3-{[({[4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Benzoate

[0378] Example 15 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and methyl 3-isocyanatobenzoate(0.0241 g) to give the title compound (0.037 g). LC-MS (System A): Rt2.32 mins, Mass Spectrum m/z 452 [MH⁺].

Example 16N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-[4-(Difluoromethoxy)Phenyl]Urea

[0379] Example 16 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-(difluoromethoxy)-4-isocyanatobenzene (19.1 μl) to give the titlecompound (0.0252 g). LC-MS (System A): Rt 2.41 mins, Mass Spectrum m/z460 [MH⁺].

Example 17N-{[4-(3,4-Dichlorobenzyl)Morpholin-2-yl]methyl)-N′-(4-fluorophenyl)Urea

[0380] Example 17 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-fluoro-4-isocyanatobenzene(15.5 μl) to give the title compound (0.031 μg). LC-MS (System A): R_(t)2.30 mins, Mass Spectrum m/z 421 [MH⁺].

Example 18N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-[3-(methylthio)Phenyl]Urea

[0381] Example 18 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-isocyanato-3-(methylthio)benzene (18.8 μl) to give the title compound(0.0352 g). LC-MS (System A): Rt 2.41 mins, Mass Spectrum m/z 440 [MH⁺].

Example 19 N-(4-Chlorophenyl)-N′-{[4-(1naphthylmethyl)Morpholin-2-yl]Methyl}Urea

[0382] To a stirred solution of Intermediate 9 (0.01 g) inN,N-dimethylformamide (1 ml) was added 1-(chloromethyl)naphthalene (6.1μl). The mixture was stirred at 22° C. for 24 h beforetris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.01 g@4.46mmol/g) and polystyrene methyl isocyanate (Argonaut Technologies, 0.033g@1.39 mmol/g) was added. Stirring was continued for a further 2 hbefore the mixture was purified by solid phase extraction (Isolute SCXsulphonic acid column), eluting with methanol followed by 10% 0.880ammonia solution in methanol. The basic fraction was evaporated in vacuoto give the title compound (0.003 g). LC/MS (System A) R_(t) 2.82 min,Mass Spectrum m/z 4140 [MH⁺].

Example 20N-(4-Bromophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0383] Example 20 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-bromo-4-isocyanatobenzene(0.027 g) to give the title compound (0.033 g). LC-MS (System A): Rt2.49 mins, Mass Spectrum m/z 472 [MH⁺].

Example 21N-(4-Chlorophenyl)-N′-[4-(3-iodobenzyl)Morpholin-2-yl]Methyl}Urea

[0384] Example 21 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and1-(bromomethyl)-3-iodobenzene (0.0121 g) to give the title compound(0.0087 g). LC-MS (System A): Rt 2.83 mins, Mass Spectrum m/z 486 [MH⁺].

Example 22N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-[3-(trifluoromethyl)Phenyl]Urea

[0385] Example 22 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-isocyanato-3-(trifluoromethyl)benzene (18.8 μl) to give the titlecompound (0.0112 g). LC-MS (System A): Rt 2.56 mins, Mass Spectrum m/z462 [MH⁺].

Example 23N-(4-Chlorophenyl)-N′-{[4-(2-naphthylmethyl)Morpholin-2-yl]Methyl}Urea

[0386] Example 23 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and2-(bromomethyl)naphthalene (0.009 g) to give the title compound (0.0052g). LC-MS (System A): R_(t) 2.81 mins, Mass Spectrum m/z 410 [MH⁺].

Example 24N-{[4-(3,4-Dichlorobenzyl)Morpholin-2-yl]Methyl}N′-(2,6-dichloropyridin-4-yl)Urea

[0387] Example 24 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and2,6-dichloro-4-isocyanatopyridine (0.0258 g) to give the title compound(0.0165 g). LC-MS (System A): R_(t) 2.46 mins, Mass Spectrum m/z 463[MH⁺].

Example 25N-(4-Cyanophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0388] Example 25 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 4-isocyanatobenzonitrile(0.0196 g) to give the title compound (0.0325 g). LC-MS (System A):R_(t) 2.29 mins, Mass Spectrum m/z 419 [MH⁺].

Example 26N-{[4-(3-Chlorobenzyl)morpholin-2-yl]Methyl}-N′-(4-chlorophenyl)Urea

[0389] Example 26 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and1-(bromomethyl)-3-chlorobenzene (5.4 μl) to give the title compound(0.0023 g). LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 394 [MH⁺].

Example 27N-[(4-But-3-enylmorpholin-2-yl)methyl]-N′-(4-chlorophenyl)Urea

[0390] Example 27 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and 4-bromobut-1-ene (4.1 μl)to give the title compound(0.0027 g).

[0391] LC-MS (System A): Rt 2.34 mins, Mass Spectrum m/z 324 [MH⁺].

Example 28N-(4-Chlorophenyl)-N′-({4-[2-(phenylthio)Ethyl]Morpholin-2-ylmethyl)Urea

[0392] Example 28 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and[(2-bromoethyl)thio]benzene (0.0089 g) to give the title compound(0.0023 g). LC-MS (System A): R_(t) 2.77 mins, Mass Spectrum m/z 406[MH⁺].

Example 29N-(4-Chlorophenyl)-N′-[4-(2-methoxyethyl)Morpholin-2-yl]Methyl}Urea

[0393] Example 29 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and 1-bromo-2-methoxyethane(3.8 μl) to give the title compound (0.0041 g). LC-MS (System A): R_(t)2.22 mins, Mass Spectrum m/z 328 [MH⁺].

Example 30N{[4-(1,1′-Biphenyl-4-ylmethyl)Morpholin-2-yl]Methyl}N′-(4-chlorophenyl)Urea

[0394] Example 30 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and4-(chloromethyl)-1,1′-biphenyl (0.0083 g) to give the title compound(0.0052 g). LC-MS (System A): Rt 2.95 mins, Mass Spectrum m/z 436 [MH⁺].

Example 31N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(1-naphthyl)Urea

[0395] Example 31 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-isocyanatonaphthalene (19.6μl) to give the title compound (0.0304 g). LC-MS (System A): Rt 2.43mins, Mass Spectrum m/z 444 [MH⁺].

Example 32N-(1,1′-Biphenyl-4-yl)-N′-{[4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}Urea

[0396] Example 32 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 4-isocyanato-1,1′-biphenyl(0.0266 g) to give the title compound (0.0314 g). LC-MS (System A):R_(t) 2.65 mins, Mass Spectrum m/z 470 [MH⁺].

Example 33N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-(4-phenoxyphenyl)Urea

[0397] Example 33 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-phenoxybenzene(24.6 μl) to give the title compound (0.0171 g). LC-MS (System A): R_(t)2.62 mins, Mass Spectrum m/z 486 [MH⁺].

Example 34N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-{4-[(Trifluoromethyl)Thio]Phenyl}Urea

[0398] Example 34 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-isocyanato-4-[(trifluoromethyl)thio]benzene (21.9 μl) to give thetitle compound (0.0122 g). LC-MS (System A): R_(t) 2.70 mins, MassSpectrum m/z 494 [MH⁺].

Example 35N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-[4-(Trifluoromethoxy)Phenyl]Urea

[0399] Example 35 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and1-isocyanato-4-(trifluoromethoxy)benzene (20.6 μl) to give the titlecompound (0.0371 g). LC-MS (System A): R_(t) 2.57 mins, Mass Spectrumm/z 478 [MH⁺].

Example 36N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-[4-(dimethylamino)Phenyl]Urea

[0400] Example 36 was prepared in an analogous manner to Example 1 usinga mixture of Intermediate 3 (0.025 g) and4-isocyanato-N,N-dimethylaniline (0.0221 g) to give the title compound(0.031 g). LC-MS (System A): R_(t) 1.68 mins, Mass Spectrum m/z 437[MH⁺].

Example 37N-(4-Chlorophenyl)-N′-({4-[(5-chlorothien-2-yl)Methyl]Morpholin-2-yl}Methyl)Urea

[0401] Example 37 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and2-chloro-5-(chloromethyl)thiophene (0.0068 g) to give the title compound(0.0098 g). LC-MS (System A): R_(t) 2.84 mins, Mass Spectrum m/z 400[MH⁺].

Example 38N-(4-Chlorophenyl)-N′-{[4-(4-vinylbenzyl)Morpholin-2-yl]Methyl}Urea

[0402] Example 38 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and1-(chloromethyl)-4-vinylbenzene (0.0062 g) to give the title compound(0.0071 g). LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 386 [MH⁺].

Example 392-{2-[({[(4-Chlorophenyl)Amino]Carbonyl}amino)Methyl]Morpholin-4-yl}EthylBenzoate

[0403] Example 39 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and 2-bromoethyl benzoate(6.51 μl) to give the title compound (0.007 g). LC-MS (System A): R_(t)2.69 mins, Mass Spectrum m/z 418 [MH⁺].

Example 40N-(4-Chlorophenyl)-N′-({4-[2-(4-fluorophenoxy)Ethyl]Morpholin-2-yl}Methyl)Urea

[0404] Example 40 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and1-(2-bromoethoxy)-4-fluorobenzene (0.0089 g) to give the title compound(0.007 g). LC-MS (System A): R_(t) 2.69 mins, Mass Spectrum m/z 408[MH⁺].

Example 41N-(4-Chlorophenyl)-N′-({4-[4-(4-chlorophenyl)-4-oxobutyl]Morpholin-2-yl)Methyl}Urea

[0405] Example 41 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and4-chloro-1-(4-chlorophenyl)butan-1-one (0.0089 g) to give the titlecompound (0.0043 g). LC-MS (System A): Rt 2.83 mins, Mass Spectrum m/z450 [MH⁺].

Example 42N-(4-Chlorophenyl)-N′-{[4-(3,4-dichlorobenzoyl)Morpholin-2-yl]Methyl}Urea

[0406] To a stirred solution of Intermediate 9 (0.05 g) was added asolution of 3,4-dichlorobenzoyl chloride (42.7 mg) inN,N-dimethylformamide (7 ml). The mixture was stirred at 22° C. for 15 hbefore the solvent was evaporated in vacuo. The residue was purified byeluting through a 1 g silica solid phase extraction cartridge (VarianBondelut), eluting sequentially with dichloromethane, ether, ethylacetate, acetone, acetonitrile and methanol, to give the title compoundas a white solid (0.080 g). LC/MS (System A) R_(t) 3.10 min, MassSpectrum m/z 442 [MH⁺].

Example 43N′-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N-(4-fluorophenyl)-N-methylurea

[0407] 4-Fluoro-N-methylaniline (0.007 ml) was added to a solution ofIntermediate 10 (0.025 g) in anhydrous pyridine (1 ml). The mixture washeated at ? 110° C. in a thick walled glass vial (Reactivial) for 20 h.The mixture was evaporated to remove the pyridine, and partitionedbetween ethyl acetate (10 ml) and saturated aqueous sodium bicarbonatesolution (10 ml). The organic layer was washed with further sodiumbicarbonate (10 ml×5), brine (10 ml), dried (MgSO₄), concentrated invacuo. The residue was purified by chromatography on silica gel(Trikonex flash tube 2002, 2 g), eluting with 70% ethyl acetate incyclohexane to give the title compound as a pale yellow gum 0.014 g.LCMS (system A) R_(t) 2.52 min, Mass Spectrum m/z 426 [MH⁺].

Example 44 Ethyl{2-[({[(4-chlorophenyl)Amino]Carbonyl}Amino)Methyl]Morpholin-4-yl}(Phenyl)Acetate

[0408] Example 44 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and ethylbromo(phenyl)acetate (0.029 g) to give the title compound (0.0372 g).LC-MS (System A): Rt 3.43 mins, Mass Spectrum m/z 432 [MH⁺].

Example 452-{2-[({[(4-Chlorophenyl)amino]carbonylamino)methyl]morpholin-4-yl}-2-phenylacetamide

[0409] Example 45 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and 2-bromo-2-phenylacetamide(0.028 g) to give the title compound (0.0296 g). LC-MS (System A): R_(t)2.75 mins, Mass Spectrum m/z 401 [MH⁺].

Example 46N-(4-Chlorophenyl)-N′-{[4-(cyanomethyl)Morpholin-2-yl]Methyl}Urea

[0410] Example 46 was prepared in an analogous manner to Example 19using a mixture of Intermediate 9 (0.01 g) and bromoacetonitrile (2.8μl) to give the title compound (0.0039 g).

[0411] LC-MS (System A): R_(t) 2.79 mins, Mass Spectrum m/z 309 [MH⁺].

Example 47N-(4-Chlorobenzyl)-N′-{[4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}Urea

[0412] A suspension of 4-{[(polystyrene resin)methyl]thio}phenyl4-nitrophenyl carbonate (Prepared as described in Tetrahedron Lett.(1998), 39(22), 3631-3634, 1.5 g @ 0.99 mmol/g) in N,N-dimethylformamide(15 ml) was shaken with Intermediate 3 (0.80 g) at 22° C. for 1 h. Theresin was filtered, washed with N,N-dimethylformamide (×2),dichloromethane (×3) and N,N-dimethylformamide. The resin was againshaken with N,N-dimethylformamide (15 ml) and Intermediate 3 (0.80 g) at22° C. for 1 h before being filtered, washed with N,N-dimethylformamide(×2), dichloromethane (×3) and ether (×2) and dried in vacuo to give theintermediate resin 4-{[(polystyrene resin)methyl]thio}phenyl[4-(3,4-dichlorobenzyl)morpholin-2-yl]methylcarbamate as orange beads.To a sample of this resin (50 mg) in a test tube was added4-chlorobenzylamine (9.6 μl) and 1 drop of 1-methyl-2-pyrrolidinone, andthe mixture was placed into a microwave oven and heated at full power(600W) for 5 min. Dichloromethane (2 ml) and formylpolystyrene resinwere added, and the mixture was shaken at 22° C. for 18 h. Thesuspension was poured onto a 1 g solid phase extraction (Isolute SCXsulphonic acid) column which was then washed with methanol beforeeluting with 10% 0.880 ammonia solution in methanol. The basic fractionwas evaporated in vacuo to give a cream solid which was further purifiedby eluting through a 1 g silica solid phase extraction cartridge (VarianBondelut) eluting sequentially with dichloromethane, ether, ethylacetate, acetone, acetonitrile and methanol, to give the title compoundas a white solid (4.7 mg). LC/MS (System A) R_(t) 2.70 min, MassSpectrum m/z 442 [MH⁺].

Example 48N-(3-Chlorobenzyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0413] Example 48 was prepared in an analogous manner to Example 47using a mixture of Intermediate 3 (0.025 g) and1-(3-chlorophenyl)methanamine (9.6 μl) to give the title compound(0.0092 g). LC-MS (System A): R_(t) 2.73 mins, Mass Spectrum m/z 442[MH⁺].

Example 49N-(2-Chlorobenzyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea

[0414] Example 49 was prepared in an analogous manner to Example 47using a mixture of Intermediate 3 (0.025 g) and1-(2-chlorophenyl)methanamine (9.6111) to give the title compound (0.008g). LC-MS (System A): Rt 2.74 mins, Mass Spectrum m/z 442 [MH⁺].

Example 50N-(4-Chlorophenyl)-N′-[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea(ISOMER 1)

[0415] Chiral separation from the racemic mixture of Example 14:

[0416] Example 14 (racemic mixture, 0.040 g) was separated into itssingle enantiomers of unknown configuration with a chiral preparativeHPLC system. The separation was carried out using a Chiralpak AD column(2 cm×25 cm), eluting with 60% ethanol in heptane (15 ml/min over 25mins, UV detection λ=215 nm) to give the title compound as a white solid(0.012 g).

[0417] Preparative HPLC retention time 7.5 min.

Example 51N-(4-Chlorophenyl)-N′-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Urea(ISOMER 2)

[0418] Example 51 was prepared in an analogous manner to Example 50yielding the title compound as a white solid (0.012 g). Preparative HPLCretention time 11 min.

Example 52N-[3-({[({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)Phenyl]AcetamideFormate

[0419] Example 52 was prepared in an analogous manner to Example 43 fromIntermediate 10 (0.04 g) and 3-acetamidobenzylamine (0.022 g), andpurified by Mass Directed Automated Preparative HPLC to yield the titlecompound (0.008 g).

[0420] LC-MS (System A) R_(t) 2.47 mins. Mass Spectrum m/z 465 [MH⁺].

Example 534-({[({[4-(3,4-Dichlorobenzyl)Morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)Benzamide

[0421] Example 53 was prepared in an analogous manner to Example 47 fromIntermediate 3 (0.025 g) and 4-aminomethylbenzamide (0.016 g) to yieldthe title compound (0.0083 g).

[0422] LC-MS (System A) R_(t) 2.16 mins. Mass Spectrum m/z 451, 453[MH⁺].

Example 544-({[({[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)Benzamide

[0423] Example 54 was prepared in an analogous manner to Example 43 fromIntermediate 13 (0.079 g) and 4-aminomethylbenzamide (0.032 g) usingN,N-dimethylformamide as solvent to yield the title compound (0.0837 g).

[0424] LC-MS (System A) R_(t) 2.27 mins. Mass Spectrum m/z 451, 453[MH⁺].

[0425] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: R_(t) 41.8min.

Example 554-({[({[(2R)-4-(3,4-Dichlorobenzyl)Morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)Benzamide

[0426] Example 55 was prepared in an analogous manner to Example 43 fromIntermediate 14 (0.109 g) and 4-aminomethylbenzamide (0.045 g) usingN,N-dimethylformamide as solvent to yield the title compound (0.0828 g).

[0427] LC-MS (System A) R_(t) 2.27 mins. Mass Spectrum m/z 451, 453[MH⁺].

[0428] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 36.7 min.

Example 56N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-prop-2-ynylurea

[0429] Example 56 was prepared in an analogous manner to Example 43 fromIntermediate 10 (0.040 g) and propargylamine (0.006 g) usingdichloromethane and triethylamine at a temperature of 22° C. to yieldthe title compound (0.028 g).

[0430] LC-MS (system A) R_(t) 2.22 mins. Mass Spectrum m/z 356 [MH⁺].

[0431] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: R_(t) 12.25min and 14.1 min.

Example 57N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-prop-2-ynylurea

[0432] Example 57 was prepared in an analogous manner to Example 43 fromIntermediate 13 (0.1 g) and propargylamine (0.014 g) usingdichloromethane and triethylamine at a temperature of 22° C. to yieldthe title compound (0.064 g).

[0433] LC-MS (System A) R_(t) 2.40 mins. Mass Spectrum m/z 356 [MH⁺].

[0434] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 14.14 min.

Example 58N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-prop-2-ynylurea

[0435] Example 58 was prepared in an analogous manner to Example 43 fromIntermediate 14 (0.12 g) and propargylamine (0.014 g) usingdichloromethane and triethylamine at a temperature of 22° C. to yieldthe title compound (0.057 g).

[0436] LC-MS (System A) Rt 2.37 mins. Mass Spectrum m/z 356 [MH⁺].

[0437] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 12.26 min.

Examples 59-122

[0438] Name Preparation analogous to Characterising Data 59N-benzyl-N′-{[(2R,5S)-4-(3,4- Example 1 LC-MS (System A):dichlorobenzyl)-5- Rt 2.89 mins. methylmorpholin-2-yl]methyl}urea MassSpectrum m/z 422 [MH⁺]. 60 N-benzyl-N′-{[(2S,5R)-4-(3,4- Example 1 LC-MS(System A): dichlorobenzyl)-5- Rt 2.68 mins.methylmorpholin-2-yl]methyl}urea Mass Spectrum m/z 422 [MH⁺]. Normalphase Analytical HPLC Rt 14.2 mins. 61 4-({[({[4-(3,4- Example 47 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.40 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 487methyl)benzenesulfonamide [MH⁺]. 62 N′-{[4-(3,4- Example 43 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.06 mins.yl]methyl}-N-methyl-N-pyridin-4- Mass Spectrum m/z 409 ylurea [MH⁺]. 63N-{[(2S)-4-(3,4- Example 50 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.68 mins. yl]methyl}-N′-(4- Chiralpreparative HPLC, methoxybenzyl)urea eluent 20% ethanol/n- heptane, Rt18.7 min. 64 N,N′-bis{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.79 mins. yl]methyl}urea Mass Spectrumm/z 576 [MH⁺]. 65 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.42 mins. yl]methyl}-N′-(3,4- MassSpectrum m/z 468, dimethoxybenzyl)urea 470 [MH⁺]. 66N-(3-cyanobenzyl)-N′-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.48 mins. yl]methyl}urea Mass Spectrumm/z 433, 435 [MH⁺]. 67 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 1.88 mins. yl]methyl}-N′-(pyridin-3- MassSpectrum m/z 409, ylmethyl)urea 411 [MH⁺]. 68 N-{[4-(3,4- Example 47LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.54 mins.yl]methyl}-N′-(3- Mass Spectrum m/z 438, methoxybenzyl)urea 440 [MH⁺].69 N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2-Rt 2.88 mins. yl]methyl}-N′-[3- Mass Spectrum m/z 492,(trifluoromethoxy)benzyl]urea 494 [MH⁺]. 70 N-{[4-(3,4- Example 47 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.83 mins. yl]methyl}-N′-[4-Mass Spectrum m/z 476, (trifluoromethyl)benzyl]urea 478 [MH⁺]. 71N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt2.59 mins. yl]methyl}-N′-(4-(1,2,3-thiadiazol-4- Mass Spectrum m/z 492,yl)benzyl]urea 494 [MH⁺]. 72 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.88 mins. yl]methyl}-N′-[4- MassSpectrum m/z 492, (trifluoromethoxy)benzyl]urea 494 [MH⁺]. 73N-(3,5-dichlorobenzyl)-N′-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.92 mins. yl]methyl}urea Mass Spectrumm/z 476, 478, 480 [MH⁺]. 74 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.82 mins. yl]methyl}-N′-[3- MassSpectrum m/z 476, (trifluoromethyl)benzyl]urea 478 [MH⁺]. 75 N-{[4-(3,4-Example LC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt 2.88 mins.yl]methyl}-N′-(2,4- Mass Spectrum m/z 444, difluorobenzyl)urea 446[MH⁺]. 76 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.65 mins. yl]methyl}-N′-(3,4- MassSpectrum m/z 444, difluorobenzyl)urea 446 [MH⁺]. 77 N-{[4-(3,4- Example47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.58 mins.yl]methyl}-N′-(3-fluorobenzyl)urea Mass Spectrum m/z 426, 428 [MH⁺]. 78N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt2.51 mins. yl]methyl}-N′-(1H-indol-5- Mass Spectrum m/z 447,ylmethyl)urea 449 [MH⁺]. 79 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.50 mins. yl]methyl}-N′-(1H-indol-4-Mass Spectrum m/z 447, ylmethyl)urea 449 [MH⁺]. 80N-(3,4-dichlorobenzyl)-N′-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.89 mins. yl]methyl}urea Mass Spectrumm/z 476, 478, 480 [MH⁺]. 81 3-({[({[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 131 Rt 2.29 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 465,methyl)-N-methylbenzamide 467 [MH⁺]. 82 N-{[4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2- 136 Rt 2.77 mins.yl]methyl}-N′-(2,3-dihydro-1- Mass Spectrum m/z 450,benzofuran-5-ylmethyl)urea 452 [MH⁺]. 83 N-{[4-(3,4- Example 47 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.27 mins.yl]methyl}-N′-[(5-methylisoxazol-3- Mass Spectrum m/z 413,yl)methyl]urea 415 [MH⁺]. 84 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.82 mins. yl]methyl}-N′-[2- MassSpectrum m/z 492, (trifluoromethoxy)benzyl]urea 494 [MH⁺]. 85 methyl3-({[({[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2-Rt 2.55 mins. yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 466,methyl)benzoate 468 [MH⁺]. 86 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.78 mins. Mass yl]methyl}-N′-[2-Spectrum m/z 476, 478 (trifluoromethyl)benzyl]urea [MH⁺]. 87 N-{[4-(3,4-Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.58 mins.yl]methyl}-N′-(4-fluorobenzyl)urea Mass Spectrum m/z 426, 428 [MH⁺]. 88N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt2.55 mins. yl]methyl}-N′-(2-fluorobenzyl)urea Mass Spectrum m/z 426, 428[MH⁺]. 89 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.73 mins. yl]methyl}-N′-(4- MassSpectrum m/z 466, isopropoxybenzyl)urea 468 [MH⁺]. 90 N-{[4-(3,4-Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.59 mins.yl]methyl}-N′-(2,4- Mass Spectrum m/z 468, dimethoxybenzyl)urea 470[MH⁺]. 91 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.60 mins. yl]methyl}-N′-[2-(4- MassSpectrum m/z 452, methoxyphenyl)ethyl]urea 454 [MH⁺]. 92N-[2-(4-tert-butoxyphenyl)ethyl]-N′- Example 47 LC-MS (System A):{[4-(3,4-dichlorobenzyl)morpholin- Rt 2.84 mins. 2-yl]methyl}urea MassSpectrum m/z 494, 496 [MH⁺]. 93 N-{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.58 mins. yl]methyl}-N′-(thien-2- MassSpectrum m/z 414 ylmethyl)urea [MH⁺]. 94 N-{[4-(3,4- Example 47 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.54 mins.yl]methyl}-N′-(2-thien-2- Mass Spectrum m/z 428, ylethyl)urea 430 [MH⁺].95 N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2-Rt 2.26 mins. yl]methyl}-N′-[3- Mass Spectrum m/z 451,(dimethylamino)benzyl]urea 453 [MH⁺]. 96 N-{[4-(3,4- Example 47 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.26 mins.yl]methyl}-N′-propylurea Mass Spectrum m/z 360, 362 [MH⁺]. 97N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt2.67 mins. yl]methyl}-N′-[2- Mass Spectrum m/z 454,(methylthio)benzyl]urea 456 [MH⁺]. 98 N-(4-cyanobenzyl)-N′-{[4-(3,4-Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.47 mins.yl]methyl}urea Mass Spectrum m/z 433, 435 [MH⁺]. 99 2-{[({[4-(3,4-Example 43 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.35 mins.yl]methyl}amino)carbonyl]amino}- Mass Spectrum m/z 438N-methylethanesulfonamide [MH⁺]. 100 N-{[4-(3,4- Example 43 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.14 mins.yl]methyl}-N′-(4-hydroxybut-2- Mass Spectrum m/z 386 ynyl)urea [MH⁺].101 N-allyl-N′-{[(2S)-4-(3,4- Example 50 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.40 mins. yl]methyl}urea Chiralpreparative HPLC, eluent 20% ethanol/n- heptane, Rt 9.3 min. 102N-but-3-enyl-N′-{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.40 mins. yl]methyl}urea Mass Spectrumm/z 372 [MH⁺]. 103 N-{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.19 mins.yl]methyl}-N′-[2-(pyrrolidin-1- Mass Spectrum m/z 479ylsulfonyl)ethyl]urea [MH⁺]. 104 N′-{[4-(3,4- Example 43 LC-MS (SystemA): dichlorobenzyl)morpholin-2- Rt 2.81 mins.yl]methyl}-N-(4-methoxybenzyl)-N- Mass Spectrum m/z 452 methylurea[MH⁺]. 105 methyl 4-({[({[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.65 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 466 methyl)benzoate[MH⁺]. 106 4-({[({[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.61 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 570,methyl)-N-(1,3-thiazol-2- 572 [MH⁺]. yl)benzenesulfonamide 107N-{[4-(3,4- Example LC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt1.95 mins. yl]methyl}-N′-({5- Mass Spectrum m/z 455,[(dimethylamino)methyl]-2- 457 [MH⁺]. furyl}methyl)urea 108 N-{[4-(3,4-Example LC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt 2.52 mins.yl]methyl}-N′-[(3- Mass Spectrum m/z 445,methoxyisothiazol-5-yl)methyl]urea 447 [MH⁺]. 109 N-{[4-(3,4- ExampleLC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt 2.35 mins.yl]methyl}-N′-[(4-methyl-1,3-thiazol- Mass Spectrum m/z 429,2-yl)methyl]urea 431 [MH⁺]. 110 N-{[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.40 mins.yl]methyl}-N′-[(6-methoxypyridin-3- Mass Spectrum m/z 439,yl)methyl]urea 441 [MH⁺]. 111 5-({[({[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.10 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 452,methyl)nicotinamide 454 [MH⁺]. 112 N-{[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.14 mins. yl]methyl}-N′-(pyrazin-2-Mass Spectrum m/z 410, ylmethyl)urea 412 [MH⁺]. 113 N-{[4-(3,4- ExampleLC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt 2.26 mins.yl]methyl}-N′-(1,3-thiazol-2- Mass Spectrum m/z 415, ylmethyl)urea 417[MH⁺]. 114 N-{[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.34 mins.yl]methyl}-N′-[(2-methyl-1,3-thiazol- Mass Spectrum m/z 429,4-yl)methyl]urea 431 [MH⁺]. 115 methyl 2-({[({[4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2- 136 Rt 2.49 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 487,methyl)-4-methyl-1,3-thiazole-5- 489 [MH⁺]. carboxylate 116N-[(5-amino-1-phenyl-1H-pyrazol- Example LC-MS (System A):4-yl)methyl]-N′-{[4-(3,4- 136 Rt 2.45 mins. dichlorobenzyl)morpholin-2-Mass Spectrum m/z 489, yl]methyl}urea 491 [MH⁺]. 117 N-{[4-(3,4- ExampleLC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt 2.26 mins.yl]methyl}-N′-(1H-pyrrolo[2,3- Mass Spectrum m/z 448,b]pyridin-3-ylmethyl)urea 450 [MH⁺]. 118 N-{[4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2- 136 Rt 1.98 mins.yl]methyl}-N′-({5- Mass Spectrum m/z 471,[(dimethylamino)methyl]thien-2- 473 [MH⁺]. yl}methyl)urea 119N-{[4-(3,4- Example LC-MS (System A): dichlorobenzyl)morpholin-2- 136 Rt2.42 mins. yl]methyl}-N′-(2-furylmethyl)urea Mass Spectrum m/z 398, 400[MH⁺]. 120 N-{[4-(3,4- Example LC-MS (System A):dichlorobenzyl)morpholin-2- 136 Rt 2.21 mins.yl]methyl}-N′-[(2-methyl-2H- Mass Spectrum m/z 414,tetraazol-5-yl)methyl]urea 416 [MH⁺]. Chiral analytical HPLC, eluent 30%EtOH/n- heptane(0.1% TFA), Rt 9.99 min and 12.75 min. 121N-but-3-ynyl-N′-{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.32 mins. yl]methyl}urea Mass Spectrumm/z 370 [MH⁺]. 122 N-{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.46 mins. yl]methyl}-N′-[3- MassSpectrum m/z 500 (phenylsulfonyl)propyl]urea [MH⁺].

Example 1234-({[({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)BenzoicAcid Compound with N,N,N-triethylamine (1:1)

[0439] Sodium hydroxide (0.09 g) was added to a stirred solution ofExample 105 (0.522 g) in a mixture of water (5 ml) and methanol (5 ml)at 20° C., and stirring was continued at 20° C. for 18 h. The pH of themixture was adjusted to approximately 6 by the addition of 2M aqueoussodium hydroxide and the mixture was applied in two equal portions toion exchange cartridges (10 g Isolute SCX pre-conditioned withmethanol). Elution with methanol (3 column volumes) followed 10%triethylamine in methanol (2 column volumes) and evaporation of thefirst basic fractions in vacuo gave the title compound as a tan solid(0.468 g). LCMS (System A) R_(t) 2.60 min Mass Spectrum m/z 452 [MH⁺]

Example 1244-({[({[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)BenzamideHydrochloride

[0440] 4.0M hydrogen chloride in 1,4-dioxane (2.0 ml) was added to astirred solution of Example 54 (0.100 g) in methanol (10 ml), andstirring was continued at 22° C. for 1 h. The solvents were evaporatedunder a stream of nitrogen and the residue re-dissolved in methanol (4ml). Toluene (4 ml) was added, and the solvents were again evaporatedunder a stream of nitrogen. The residue was re-dissolved in methanol (4ml), toluene (4 ml) added, and the solvents again evaporated under astream of nitrogen. The white residue was triturated in ether and thesolvent evaporated under a stream of nitrogen before being dried invacuo to give the title compound as a white solid (0.117 g).

[0441] LCMS (System A) R_(t) 2.25 min Mass Spectrum m/z 451 [MH⁺]

[0442]¹H NMR (D6 DMSO): 11.45δ(1H, br.s, NH⁺), 7.97-7.92δ(2H, d+br.s,Aromatic CH+NH) 7.82δ(2H, ½AA‘BB’, 2×Aromatic CH), 7.75δ(1H, d, AromaticCH), 7.59δ(1H, dd, Aromatic CH), 7.32δ(1H, br.s, NH), 7.28δ(2H, ½A‘BB’,2×Aromatic CH), 6.62, 6.28δ(2H, 2×v.br.s, CONH₂), 4.35δ(2H, AB, CH₂),4.25δ(2H, s, CH₂), 3.95δ(1H, dd, CH), 3.88-3.79δ(2H, m, 2×CH), 3.28δ(1H,br.d, CH), 3.25-3.18δ(2H, br.m, 2×CH), 3.09δ(1H, dd, CH), 3.00δ(1H,br.m, CH), 2.78δ(1H, m, CH)

Example 125N-{[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-N′-prop-2-ynylurea

[0443] A solution of Intermediate 22 (0.024 g) in dichloromethane (1 ml)was stirred with Intermediate 20 (0.033 g) and N,N-diisopropylethylamine(0.022 ml) for 3 h at 23° C. The solvent was removed in vacuo and theresidue was purified by solid phase extraction (Isolute SCX sulphonicacid column) eluting with methanol followed by 10% 0.880 ammoniasolution in methanol. The basic fraction was concentrated in vacuo, andthe residue was dissolved in dichloromethane (5 ml), and the solutionshaken with polystyrene methyl isocyanate resin (Argonaut technologies,0.256 g, 1.43 mmol/g) for 16 h. The solution Was drained from the resinand the resin washed with dichloromethane (8 ml); the combined filtrateand washings were concentrated in vacuo to give the title compound as apale yellow gum (0.02 g).

[0444] LC/MS (System A) R_(t) 2.17 min, Mass spectrum m/z 356 [MH⁺].

Example 126N-({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-N′-prop-2-ynylurea

[0445] Example 126 was prepared in an analogous manner to Example 125from Intermediate 23, (0.030 g). Further purification using a silica gelsolid phase extraction cartridge (1 g Varian Bond Elut), eluting with0-5% methanol in ethyl acetate, gave the title compound as a clear gum(0.025 g).

[0446] LC/MS (System A) R_(t) 1.95 min Mass spectrum m/z 328 [MH⁺].

Example 127N-{[(2S)-4-(3-chlorobenzyl)Morpholin-2-yl]methyl}-N′-prop-2-ynylurea

[0447] Example 127 was prepared in an analogous manner to Example 125from Intermediate 19 (0.029 g). Further purification using a silica gelsolid phase extraction cartridge (1 g Varian Bond Elut), eluting with0-5% methanol in ethyl acetate, gave the title compound as a clear gum(0.021 g).

[0448] LC/MS (System A) R_(t) 1.93 min Mass spectrum m/z 322 [MH⁺].

Examples 128-130

[0449] Name Preparation analogous to Characterising Data 1283-({[({[4-(3,4- Example 131 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.32 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 479,methyl)-N,N-dimethylbenzamide 481 [MH⁺]. 129 3-({[({[4-(3,4- Example 131LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.33 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 479,methyl)-N-ethylbenzamide 481 [MH⁺]. 130 N-cyclopropyl-3-({[({[4-(3,4-Example 131 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.34 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 491, methyl)benzamide493 [MH⁺].

Example 1314-({[({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)-N-methylbenzamide

[0450] Example 123 (0.050 g), 1-hydroxybenzotriazole (0.066 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.116 g)were stirred in N,N-dimethylformamide (4.2 ml) andN,N-diisopropylethylamine (0.132 ml) was added to the mixture. Stirringwas continued at 20° C. until a clear solution was obtained. 2.0Mmethylamine in tetrahydrofuran (0.379 ml) was added to a portion of themixture (1.0 ml) and the mixture was stirred at 20° C. under nitrogenfor 17 h. The mixture was applied in two equal portions to ion exchangecartridges (2×2 g Isolute SCX pre-conditioned with methanol). Elutionwith methanol (3 column volumes) followed by 10% 0.880 ammonia inmethanol (2 column volumes) and evaporation of the basic fractions invacuo gave the crude product. Purification by Biotage flashchromatography on a silica gel cartridge (8 g), eluting with 100:8:1dichloromethane/ethanol/0.880 ammonia, gave the title compound as awhite solid (0.0124 g).

[0451] LCMS (System A) R, 2.22 min, Mass Spectrum m/z 465 [MH⁺].

[0452] Chiral analytical HPLC, eluent 15% ethanol in n-heptane, Rt 24.0min and 27.7 min.

Examples 132-135

[0453] Preparation Name analogous to Characterising Data 1324-({[({[4-(3,4- Example 131 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.30 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 479, 481 [MH⁺].methyl)-N,N-dimethylbenzamide 133 4-({[({[4-(3,4- Example 131 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.28 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 479, 481 [MH⁺].methyl)-N-ethylbenzamide 134 N-cyclopropyl-4-({[({[4-(3,4- Example 131LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.26 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 491, 493 [MH⁺].methyl)benzamide 135 N-{[3-(4-chlorophenyl)isoxazol-5- Example 136 LC-MS(System A): yl]methyl}-N′-{[(2S)-4-(3,4- Rt 2.98 mins.dichlorobenzyl)morpholin-2- Mass Spectrum m/z 509, 511 [MH⁺].yl]methyl}urea

Example 136N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}-N′-[(2-methyl-2H-tetraazol-5-yl)Methyl]Urea

[0454] Intermediate 30 (0.041 g) was added to a stirred solution ofIntermediate 29(0.110 g) in N,N-dimethylformamide (2 ml) at 22° C., andN,N-diisopropylethylamine (0.052 ml) was added. After stirring for 20 h,the mixture was applied in two equal portions to ion exchange cartridges(10 g Isolute SCX pre conditioned with methanol). Elution with methanol(3 column volumes) followed by 10% 0.880 ammonia in methanol (2 columnvolumes) and evaporation of the first basic fractions in vacuo gave thecrude product. Purification by Biotage flash chromatography on silicagel (8 g cartridge), eluting with 100:8:1 dichloromethane/ethanol/0.880ammonia, gave the title compound as a white solid, (0.0828 g).

[0455] LC/MS (System A) R_(t) 2.19 min Mass Spectrum m/z 414 [MH⁺].

[0456] Chiral analytical HPLC, eluent 30% ethanol/0.1% trifluoroaceticacid in n-heptane, Rt 10.1 min.

Examples 137-144

[0457] Name Preparation analogous to Characterising Data 1374-(2-{[({[(2S)-4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.38 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 501,ethyl)benzenesulfonamide 503 [MH⁺]. 138 3-({[({[(2S)-4-(3,4- Example 136LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.28 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 465,methyl)-N-methylbenzamide 467 [MH⁺]. 139N-cyclopropyl-3-({[({[(2S)-4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.57 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 527,methyl)benzenesulfonamide 529 [MH⁺]. 140 N-{[(2S)-4-(3,4- Example 136LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.33 mins.yl]methyl}-N′-[(4-methyl-1,3-thiazol- Mass Spectrum m/z 429,2-yl)methyl]urea 431 [MH⁺]. 141 N-{[(2S)-4-(3,4- Example 136 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.23 mins.yl]methyl}-N′-(1,3-thiazol-2- Mass Spectrum m/z 415, ylmethyl)urea 417[MH⁺]. 142 N-{[(2S)-4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.73 mins. yl]methyl}-N′-{[3-(4- MassSpectrum m/z 505, methoxyphenyl)isoxazol-5- 507 [MH⁺]. yl]methyl}urea143 tert-butyl 4-({[({[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.69 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 515methyl)piperidine-1-carboxylate [MH⁺]. 144N-cyclopropyl-4-({[({[(2S)-4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.54 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 527,methyl)benzenesulfonamide 529 [MH⁺].

Example 145N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}N′-[3-(ethylsulfonyl)Propyl]Urea

[0458] Intermediate 40 (0.0225 g) and N,N-diisopropylethylamine (0.021ml) were added to a solution of Intermediate 10 (0.044 g) indichloromethane (3 ml), and the mixture was shaken at 22° C. for 19 h.Formyl polystyrene scavenging resin (2.95 mmol/g, 0.02 g) was added andthe mixture shaken for 2 h. The mixture was filtered, the resin washedwith dichloromethane, and the filtrate applied directly to a sulphonicacid ion exchange cartridge (2 g Isolute SCX). Elution with methanolfollowed by 10% 0.880 ammonia in methanol gave the crude product (0.04g). Purification by chromatography on silica gel (Varian Bond Elut 1 gcartridge), eluting with dichloromethane, ether, ethyl acetate, andacetone, gave the title compound (0.029 mg). LC-MS (System A) R_(t) 2.22mins Mass Spectrum m/z 452 [MH⁺].

Examples 146-159

[0459] Name Preparation analogous to Characterising Data 146N-{[(2S)-4-(3,4- Example 145 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.30 mins. yl]methyl}-N′-[3- MassSpectrum m/z 466 (isopropylsulfonyl)propyl]urea [MH⁺]. 147N-{[(2S)-4-(3,4- Example 145 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.34 mins. yl]methyl}-N′-[3- MassSpectrum m/z 466 (propylsulfonyl)propyl]urea [MH⁺]. 148N-[3-(tert-butylsulfonyl)propyl]-N′- Example 145 LC-MS (System A):{[(2S)-4-(3,4- Rt 2.41 mins. dichlorobenzyl)morpholin-2- Mass Spectrumm/z 480 yl]methyl}urea [MH⁺]. 149 4-({[({[(2S)-4-(3,4- Example 57 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.28 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 465methyl)-N-methylbenzamide [MH⁺]. Chiral analytical HPLC, eluent 15%ethanol in n- heptane, detection at 230 nm, Rt 29.7 min. 150N-cyclopropyl-4-({[({[(2S)-4-(3,4- Example 57 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.38 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 491 methyl)benzamide[MH⁺]. 151 ethyl 4-{[({[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.61 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 473piperidine-1-carboxylate [MH⁺]. 152 N-{[4-(3,4- Example 47 LC-MS (SystemA): dichlorobenzyl)morpholin-2- Rt 2.05 mins.yl]methyl}-N′-[2-(2-oxoimidazolidin- Mass Spectrum m/z 430,1-yl)ethyl]urea 432 [MH⁺]. 153 N-{[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.42 mins.yl]methyl}-N′-tetrahydro-2H-pyran- Mass Spectrum m/z 4-ylurea 358[MH⁺].154 N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2-Rt 1.76 mins. yl]methyl}-N′-(2-morpholin-4- Mass Spectrum m/z 431ylethyl)urea [MH⁺]. 155 ethyl 4-[({[4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.36 mins. yl]methyl}amino)carbonyl] MassSpectrum m/z 459 piperazine-1-carboxylate [MH⁺]. 156 N-{[4-(3,4- Example47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.12 mins.yl]methyl}morpholine-4- Mass Spectrum m/z 388 carboxamide [MH⁺]. 157N-{[4-(3,4- Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt2.77 mins. yl]methyl}-4-(3- Mass Spectrum m/z 481fluorophenyl)piperazine-1- [MH⁺]. carboxamide 158 N-{[4-(3,4- Example 47LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.56 mins.yl]methyl}-4-methylpiperidine-1- Mass Spectrum m/z 400 carboxamide[MH⁺]. 159 N-{[(4-(3,4- Example 47 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.31 mins.yl]methyl}-4-(2-furoyl)piperazine-1- Mass Spectrum m/z 481 carboxamide[MH⁺].

Example 160N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N′-[1-(methylsulfonyl)Piperidin-4-yl]Urea

[0460] Methane sulphonyl chloride (0.009 ml) was added to a solution ofIntermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) indichloromethane (3 ml). The solution was stirred for 5 h at 23° C. Thesolvent was removed in vacuo and the residue was purified by solid phaseextraction (Isolute SCX sulphonic acid column) eluting with methanolfollowed by 10% 0.880 ammonia solution in methanol, to give the titlecompound as a pale yellow gum (0.034 g).

[0461] LC/MS (System A) R_(t) 2.5 min Mass spectrum m/z 479 [MH⁺].

Example 161N-{[4-(3,4-dichlorobenzyl)Morpholin-2-yl]methyl}-N′-{1-[(3,5-dimethylisoxazol-4-yl)Sulfonyl]Piperidin-4-yl}Urea

[0462] Example 161 was made in an analogous manner to that of Example160 LC-MS (System A) Rt 2.86 mins. Mass Spectrum m/z 561 [MH+].

Example 162N-(1-benzoylpiperidin-4-yl)-N′-{[4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}Urea

[0463] Benzoyl choride (0.014 ml) was added to a solution ofIntermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) indichloromethane (3 ml). The solution was stirred for 5 h at 23° C. Thesolvent was removed in vacuo and the residue purified by solid phaseextraction (Isolute SCX sulphonic acid column) eluting with methanolfollowed by 10% 0.880 ammonia solution in methanol. The basic fractionwas concentrated in vacuo and the residue was further purified using asilica gel solid phase extraction cartridge (1 g Varian Bond Elut),eluting sequentially with dichloromethane, ethyl acetate, acetone,acetonitrile, and methanol, to give the title compound as a clear gum(0.024 g).

[0464] LC/MS (System A) R_(t) 2.63 min, Mass spectrum m/z 506 [MH⁺].

Examples 163-168

[0465] Name Preparation analogous to Characterising Data 163 N-{[4-(3,4-Example 47 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt mins 2.61.yl]methyl}-N′-[4- Mass Spectrum m/z 486 (methylsulfonyl)benzyl]urea[MH⁺]. 164 N′-{[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.19 mins.yl]methyl}-N-(3-hydroxypropyl)-N- Mass Spectrum m/z 453 pyridin-2-ylurea[MH⁺]. 165 N-(2-{[({[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.33 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 439ethyl)methanesulfonamide [MH⁺]. 166 4-{[({[4-(3,4- Example 43 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.21 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 403 butanamide [MH⁺].167 (2E)-4-{[({[4-(3,4- Example 43 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.18 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 402 but-2-enoic acidcompound with [MH⁺]. N,N,N-triethylamine (1:1) 168 N-(2-{[({[4-(3,4-Example 43 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.06 mins.yl]methyl}amino)carbonyl]amino} Mass Spectrum m/z 403 ethyl)acetamide[MH⁺].

Example 169N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}thiomorpholine-4-carboxamide

[0466] 1,4-Thioxane (0.02 g) and N,N-diisopropylethylamine (0.04 ml)were added to a solution of Intermediate 10 (0.08 g) in dichloromethane(2 ml). The mixture was stirred at 23° C. for 16 h, and the solventevaporated in vacuo. The residue was dissolved in dichloromethane (3ml), and the solution shaken with polystyrene methyl isocyanate resin(Argonaut Technologies, 0.14 g, 1.45 mmol/g) for 2 h. The solution wasdrained from the resin, and the resin washed with dichloromethane (6 ml)and methanol (3 ml); the combined filtrate and washings wereconcentrated in vacuo. The residue was purified further by solid phaseextraction (Isolute SCX sulphonic acid column), eluting with methanolfollowed by 10% 0.880 ammonia solution in methanol, to give the titlecompound as a pale yellow gum (0.065 g).

[0467] LCMS (system A) R, 2.55 min, Mass Spectrum m/z 404 [MH⁺].

Examples 170-174

[0468] Name Preparation analogous to Characterising Data 170 N-{[4-(3,4-Example 43 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.35 mins.yl]methyl}-N′-(1,1- Mass Spectrum m/z 436dioxidotetrahydrothien-3-yl)urea [MH⁺]. 171 N-{[4-(3,4- Example 43 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.65 mins.yl]methyl}-N′-tetrahydro-2H- Mass Spectrum m/z 418 thiopyran-4-ylurea[MH⁺]. 172 N-{[4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.89 mins. yl]methyl}-N′-[1-(4- MassSpectrum m/z 440, fluorophenyl)ethyl]urea 442 [MH⁺]. 173 N-{[4-(3,4-Example 136 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.96 mins.yl]methyl}-N′-(1-methyl-1- Mass Spectrum m/z 436, phenylethyl)urea 438[MH⁺]. 174 N-{[4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.10 mins. yl]methyl}-N′-[2-thioxo-2,3-Mass Spectrum m/z 430, dihydro-1H-imidazol-4- 432 [MH⁺]. yl)methyl]urea

Example 175N{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}thiomorpholine-4-carboxamide1,1-dioxide

[0469] Oxone (0.135 g) was added to Example 169 (0.06 g) inmethanol:water (10:1, 4 ml) at 23° C. under nitrogen, and the mixturewas stirred for 18 h. The methanol was removed in vacuo, the aqueouslayer was diluted with sodium sulphite solution (5%, 5 ml) and theproduct was extracted into dichloromethane (8 ml). The organic layer waswashed with brine (5 ml), dried (MgSO₄) and concentrated in vacuo togive the title compound as a white solid (0.055 g).

[0470] LC/MS (System A) R_(t) 2.34 min Mass spectrum m/z 436 [MH⁺].

Examples 176-181

[0471] Name Preparation analogous to Characterising Data 176 N-{[4-(3,4-Example 43 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.24 mins.yl]methyl}-4- Mass Spectrum m/z 465 (methylsulfonyl)piperazine-1- [MH⁺].carboxamide 177 N-{[4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.19 mins.yl]methyl}-2-(4-methylpyridin-2- Mass Spectrum m/z 463,yl)pyrrolidine-1-carboxamide 465 [MH⁺]. 178 N-{[(2S)-4-(3,4- Example 136LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.55 mins.yl]methyl}-N′-[2-(4- Mass Spectrum m/z 466,methoxyphenyl)-2-oxoethyl]urea 468 [MH⁺]. 179 N-{[(2S)-4-(3,4- Example136 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.69 mins.yl]methyl}-1,3,4,5-tetrahydro-2H-2- Mass Spectrum m/z 448,benzazepine-2-carboxamide 450 [MH⁺]. 180 N-{[(2S)-4-(3,4- Example 136LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.57 mins.yl]methyl}-N′-phenoxyurea Mass Spectrum m/z 410, 412 [MH⁺]. 181N-{[(2S)-4-(3,4- Example 136 LC-MS (System A):dichlorobenzyl)morpholin-2- Rt 2.64 mins.yl]methyl}-N′-(2-phenoxyethyl)urea Mass Spectrum m/z 438, 440 [MH⁺].

Example 182N-{[1-(Cyclopropylcarbonyl)piperidin-4-yl]methyl}-N′-{[(2S)-4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}Urea

[0472] Cyclopropanecarbonyl chloride (0.014 ml) was added to a solutionof Intermediate 18 (0.54 g) and N,N-diisopropylethylamine (0.063 ml) indichloromethane (2 ml). The solution was stirred for 3 h at 23° C. Thesolvent was removed in vacuo and the residue purified by solid phaseextraction (Isolute SCX sulphonic acid column) eluting with methanolfollowed by 10% 0.880 ammonia solution in methanol. The basic fractionwas concentrated in vacuo and the residue was further purified using asilica gel solid phase extraction cartridge (1 g Varian Bond Elut)eluting with 0-1% methanol in ethyl acetate, to give the title compoundas a clear gum (0.023 g).

[0473] LC/MS (system A) R_(t) 2.35 min Mass spectrum m/z 483 [MH⁺].

Example 183N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-N′-{[1-(Methylsulfonyl)Piperidin-4-yl]Methyl}Urea

[0474] Methane sulphonyl choride (0.013 ml) was added to a solution ofIntermediate 18 (0.054 g) and N,N-diisopropylethylamine (0.063 ml) indichloromethane (2 ml). The solution was stirred for 16 h at 23° C. Thesolvent was removed in vacuo and the residue purified by solid phaseextraction (Isolute SCX sulphonic acid column) eluting with methanolfollowed by 10% 0.880 ammonia solution in methanol, to give the titlecompound as a clear gum (0.035 g).

[0475] LC/MS (system A) R_(t) 2.34 min Mass spectrum m/z 493 [MH⁺].

Example 1844-({[({[4-(3,4-Dichlorobenzyl)-1,4-oxazepan-2-yl]Methyl}Amino)Carbonyl]Amino}Methyl)Benzamide

[0476] To a solution of 1,1′-carbonyldiimidazole (0.041 g) indichloromethane (2 ml) at 0° C. was added dropwise a solution ofIntermediate 41 (0.079 g) in dichloromethane (2 ml). The mixture wasstirred at 0° C. for 1 h and at 22° C. for 1 h, re-cooled toapproximately 0° C. and a solution of 4-aminomethylbenzamide (0.041 g)in a 1:1 mixture of dichloromethane and N,N-dimethylformiamide (4 ml)was added dropwise. The mixture was stirred at 0° C. for 1 h and at 22°C. for 1 h, and applied in two equal portions to ion exchange cartridges(2 g Isolute SCX pre-conditioned with methanol). Elution with methanol(3 column volumes) followed 10% 0.880 ammonia in methanol (2 columnvolumes) and evaporation of the basic fractions in vacuo gave the crudeproduct. Purification by Biotage flash chromatography on a silica gelcartridge (89), eluting with 150:8:1 dichloromethane/ethanol/0.880ammonia, gave the title compound as a white solid (0.0186 g).

[0477] LCMS (system A) R_(t) 2.22 min Mass Spectrum m/z 465 [MH⁺]

Example 1854-[({[({(2S)-4-[1-(3,4-Dichlorophenyl)Ethyl]Morpholin-2-yl}Methyl)Amino]Carbonyl}Amino)Methyl]Benzamide,Isomer II

[0478] Intermediate 35 (0.045 g) in dichloromethane (1 ml) was treatedwith N,N-diisopropylethylamine (0.021 ml) in a 5 ml vial (PierceReacti-Vial™) followed by 4-aminomethylbenzamide (0.017 g). The mixturewas sealed under nitrogen and stirred at room temperature for 18 h. Thesolution was then applied to a sulphonic acid ion exchange cartridge (2g Isolute SCX) which had been pre-treated with methanol. The cartridgewas eluted with methanol (7 column volumes) followed by 10% 0.880ammonia in methanol (3 column volumes), and the basic fractions combinedand concentrated in vacuo to give a yellow gum. Further purification bychromatography on silica gel (Varian Bond Elut 1 g cartridge), elutingwith 10% methanol in ethyl acetate, gave the title compound as a yellowgum (0.036 g).

[0479] LC/MS (System A) R_(t) 2.25 min Mass spectrum m/z 465 [MH⁺]

Example 1864-[({[({(2S)-4-[1-(3,4-Dichlorophenyl)Ethyl]Morpholin-2-yl}Methyl)Amino]Carbonyl}Amino)Methyl]Benzamide,Isomer I

[0480] Intermediate 34 (0.045 g) in dichloromethane (1 ml) was treatedwith N,N-diisopropylethylamine (0.021 ml) in a 5 ml vial (PierceReacti-Vial™) followed by 4-aminomethylbenzamide (0.017 g). The mixturewas sealed under nitrogen and stirred at room temperature for 18 h. Thesolution was then applied to a sulphonic acid ion exchange cartridge (2g Isolute SCX) which had been pre-treated with methanol. The cartridgewas eluted with methanol (7 column volumes) followed by 10% 0.880ammonia in methanol (3 column volumes), and the basic fractions combinedand concentrated in vacuo to give a yellow gum. Further purification bychromatography on silica gel (Varian Bond Elut 1 g cartridge), elutingwith 10% methanol in ethyl acetate gave the title compound as a yellowgum (0.036 g).

[0481] LC/MS (System A) R_(t) 2.27 min. Mass spectrum m/z 465 [MH⁺].

Example 1874-{[({[(2S)-4-(3,4-dichlorobenzyl)Morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}-N-Methylbutanamide

[0482] N,N′-carbonyldiimidazole (0.0132 g) was added to a stirredsolution of Intermediate 26 (0.030 g) in N,N-dimethylformamide (2 ml),and the mixture stirred at 22° C. under nitrogen for 40 min. Methylamine(2.0M solution in tetrahydrofuran, 0.102 ml) was added, and stirring wascontinued at 22° C. for 17 h. The mixture was applied directly to asulphonic acid ion exchange cartridge (2 g Isolute SCX), and eluted withmethanol followed by 10% 0.880 ammonia in methanol to give a gum (0.042g). Purification by chromatography on silica gel (1 g Varian Bond Elutcartridge), eluting with chloroform, ether, ethyl acetate, acetone, andmethanol, gave a gum (0.025 g), which was further purified by massdirected preparative HPLC to give the title compound as a colourless gum(7.2 mg).

[0483] LC-MS (System A) Rt 2.11 min Mass Spectrum m/z 417 [MH⁺].

Example 1883-{[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]Methyl}Amino)Carbonyl]Amino}-N-Methylpropane-1-Sulfonamide

[0484] Example 188 was prepared in an analogous manner to that ofExample 189

[0485] LC-MS (System A): Rt 2.20 mins Mass Spectrum m/z 453 [MH+].

Example 189N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N′-[3-(pyrrolidin-1-ylsulfonyl)Propyl]Urea

[0486] A solution of Intermediate 28 (0.027 g) in N,N-dimethylformamide(1 ml) and dichloromethane (2 ml) containing N,N-diisopropylethylamine(0.041 ml) was added to a stirred solution of Intermediate 13 (0.051 g)in dry dichloromethane (2 ml) at room temperature under nitrogen, andthe mixture was stirred at room temperature for 21 h. The mixture wasapplied directly to a sulphonic acid ion exchange cartridge (2 g IsoluteSCX) and eluted with methanol (6 column volumes) followed by 10% 880ammonia in methanol (3 column volumes); evaporation of themethanol/ammonia fractions gave the crude product (0.063 g).Purification by chromatography on silica gel (2 g Varian Bond Elutcartridge), eluting with chloroform, ether, ethyl acetate, acetone, andmethanol, gave the title compound as a gum (0.036 g).

[0487] LC-MS (System A) R_(t) 2.41 min. Mass Spectrum m/z 493 [MH⁺].

[0488] Biological Data

[0489] The compounds of the Examples were tested in the CCR-3 bindingand/or eosinophil chemotaxis assays (assays (a) and (b)) and resultswere obtained as follows: CCR-3 Binding Assay CCR-3 Eosinophil Example(pIC50) Chemotaxis Assay (fpKi) 2 7.31 3 7.16 4 7.35 5 6.93 8 6.94 136.39 14 6.18 16 6.13 18 5.84 19 5.96 21 6.02 22 6.02 23 6.08 25 6.00 265.85 34 5.70 37 5.42 38 5.72 44 4.98 47 7.18 48 7.41 52 8.75 54 7.96 7.857 8.01 136 7.8 8.3 149 7.8 7.8

[0490] Compounds of Examples 1, 6-7,9-12, 15, 17, 20, 24, 27-33, 35-36,3943, 45-46, 49-51, 53, 55-56, 58-135, 137-148 and 150-189 were alsotested in CCR-3 binding assay (assay (a)) and achieved a pIC50 valuegreater than 5.0.

[0491] Example 14 when tested in the ovalbumin sensitised guinea-pig invivo model (assay (c); 0.2-20 mg/kg), showed inhibition of lungeosinophilia and bronchial hyperreactivity.

[0492] Throughout the specification and the claims which follow, unlessthe context requires otherwise, the word ‘comprise’, and variations suchas ‘comprises’ and ‘comprising’, will be understood to imply theinclusion of a stated integer or step or group of integers but not tothe exclusion of any other integer or step or group of integers orsteps.

1. A compound of formula (I):

wherein: R¹ represents C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl-Y¹—,heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—,heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—,aryl-SO₂—Y¹—, C₁₋₄ alkyl-G-Y¹—, heteroaryl-G-aryl-Y¹—, J¹-SO₂—Y¹—,R¹⁷O(CO)—C₂₋₆ alkenyl-Y¹—, R¹⁷NHCO—Y¹—, R¹⁷NHSO₂—Y¹—, C₂₋₆ alkynyl-Y¹—,C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-Y¹—, C₁₋₄ alkyl-SO₂—Y¹—, M-Y¹—,J¹-Y¹—, J¹-CO—Y¹—, aryl-CO—Y¹— or C₃₋₈ cycloalkyl-Y¹— or C₃₋₈cycloalkenyl-Y¹—, which C₂₋₆ alkynyl and C₂₋₆ alkynyl-Y¹ may beoptionally substituted with a —OR¹⁷ group, which C₂₋₆ alkenyl may beoptionally substituted by one or more —COOR¹⁷ groups and whichcycloalkyl or cycloalkenyl may be optionally substituted by one or morehydroxyl or C₁₋₆ alkyl groups; R² represents hydrogen or C₁₋₄ alkyloptionally substituted by a hydroxy group; R³ represents hydrogen orC₁₋₄ alkyl; or R¹ and R² may together with the nitrogen atom to whichthey are attached form a group of formula J² wherein said nitrogen atomsubstitutes for either X¹ or X²; t represents 0 or
 1. X representsethylene or a group of formula CR^(e)R^(f) wherein R^(e) and R^(f)independently represent hydrogen or C₁₋₄ alkyl or R^(e) and R^(f) maytogether with the carbon atom to which they are attached form a C₃₋₈cycloalkyl group; R⁴ and R⁵ independently represent hydrogen or C₁₋₄alkyl; Z represents a bond, CO, SO₂, CR¹⁰R⁷(CH₂)_(n), (CH₂)_(n)CR¹⁰R⁷,CHR⁷(CH₂)_(n)O, CHR⁷(CH₂)_(n)S, CHR⁷(CH₂)_(n)OCO, CHR⁷(CH₂)_(n)CO,COCHR⁷(CH₂)_(n) or SO₂CHR⁷(CH₂)_(n); R⁸ represents C₁₋₆ alkyl, C₂₋₈alkenyl, aryl, heteroaryl, aryl-C₂₋₆ alkenyl-, —CN or a group of formula—Y²-J³; R⁷ represents hydrogen, C₁₋₄ alkyl, CONR⁸R⁹ or COOC₁₋₈ alkyl; aand b represent 1 or 2, such that a+b represents 2 or 3; G represents—SO₂—, —SO₂NR¹⁸—, —NR¹⁸SO₂—, —NR¹⁸CO—, CO or —CONR¹⁸—; n represents aninteger from 0 to 4; M represents a C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenylgroup fused to a monocyclic aryl or monocyclic heteroaryl group; J¹, J²and J³ independently represent a moiety of formula (K):

wherein X¹ represents oxygen, NR¹¹ or sulphur, X² represents CH₂,oxygen, NR¹² or sulphur, m¹ represents an integer from 1 to 3 and m²represents an integer from 1 to 3, provided that m¹+m² is in the rangefrom 3 to 5, also provided that when both X¹ and X² represent oxygen,NR¹¹, NR¹² or sulphur, m¹ and m² must both not equal less than 2,wherein K is optionally substituted by one or more —Y³-aryl,—Y³-heteroaryl, —Y³—CO-aryl, —COC₃₋₈ cycloalkyl, —Y³—CO-heteroaryl,—C₁₋₆ alkyl, —Y³-COOC₁₋₆ alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W,—Y³—NR¹⁵R¹⁶, —Y³—CONR¹⁵R¹⁶, hydroxy, oxo, —Y³—SO₂NR¹⁵R¹⁶, —Y³—SO₂C₁₋₈alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³—NR¹³C₁₋₆ alkyl,Y³-NR¹³SO₂C₁₋₆ alkyl, —Y³—NR¹³CONR¹⁵R¹⁶, —Y³—NR¹³COOR¹⁴ or—Y³—OCONR¹⁵R¹⁶ groups, and is optionally fused to a monocyclic aryl orheteroaryl ring; R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independentlyrepresent hydrogen or C₁₋₆ alkyl; R¹⁵ and R¹⁶ independently representhydrogen or C₁₋₄ alkyl or R¹⁵ and R¹⁶ together with the nitrogen atom towhich they are attached may form a morpholine, piperidine or pyrrolidinering; R¹⁷ and R¹⁸ independently represent hydrogen or C₁₋₄ alkyl; Wrepresents a saturated or unsaturated, non-aromatic 5-7 membered ringcontaining between 1 and 3 heteroatoms selected from nitrogen, oxygen orsulphur, optionally substituted with one or more C₁₋₆ alkyl, halogen orhydroxy groups; Y¹, Y² and Y³ independently represent a bond or a groupof formula —(CH₂)_(p)CR^(c)R^(d)(CH₂)_(q)— wherein R^(c) and R^(d)independently represent hydrogen or C₁₋₄ alkyl or R^(c) and R^(d) maytogether with the carbon atom to which they are attached form a C₃₋₈cycloalkyl group, and p and q independently represent an integer from 0to 5 wherein p+q is an integer from 0 to 5; and salts and solvatesthereof; with the following provisos; that the compound of formula (I)is not a compound of formula (I)^(a):

wherein R^(2′) represents hydrogen or lower alkyl (specifically C₁₋₄alkyl); R^(3′) represents hydrogen; X′ represents methylene or ethylene;a′ and b′ both represent 1; R^(4′) and R^(5′) both represent hydrogen;and wherein the moiety -Z′-R^(6′) represents halobenzyl, and; thecompound of formula (I) is not a compound of formula (I)^(b):

wherein R^(1″) represents a hydrogen atom, a C₁₋₄ alkyl group, a C₃₋₆cycloalkyl group, a C₃₋₆ cycloalkylC₁₋₄ alkyl group, an aryl group or anarylC₁₋₄alkyl group (particularly wherein aryl represents phenyl ornaphthyl) in which the aryl moiety of the aryl group or arylC₁₋₄ alkylgroup may be optionally substituted with a halogen atom, a C₁₋₄ alkylgroup a C₁₋₄ alkoxy group, a C₁₋₄ alkoxycarbonyl group or an aminogroup; R^(2″) represents hydrogen; R^(3″) represents hydrogen or C₁₋₆alkyl; X″ represents methylene; a″ and b″ both represent 1; R^(4″) andR^(5″) both represent hydrogen; and wherein the moiety -Z″-R^(6″)represents a C₁₋₆ alkyl group, an arylC₁₋₄ alkyl group (particularlywherein aryl represents phenyl or naphthyl), a heteroarylC₁₋₄ alkylgroup (particularly wherein heteroaryl represents 2-pyridyl, 3-pyridyl,4-pyridyl or 1H-indol-3-yl), an aryloxyC₂₋₅ alkyl group or apyrrolidinylcarbonylC₁₋₄ alkyl group in which the aryl moiety of thesaid groups may be optionally substituted with a halogen atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group, a C₁₋₆ alkoxycarbonyl group or anamino group.
 2. A compound of formula (I) according to claim 1 whereinR¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl-Y¹—,heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—,heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—,aryl-SO₂—Y¹—, C₁₋₆ alkyl-G-Y¹—, J¹-SO₂—Y¹—, R¹⁷O(CO)—C₂₋₆ alkenyl-Y¹—,C₂₋₆ alkynyl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-Y¹—, C₁₋₄alkyl-SO₂—Y¹—, M-Y¹—, J¹-Y¹—, J¹-CO—Y¹—, aryl-CO—Y¹— or C₃₋₈cycloalkyl-Y¹— or C₃₋₆ cycloalkenyl-Y¹—, which C₂₋₆ alkynyl and C₂₋₆alkynyl-Y¹ may be optionally substituted with a —OR¹⁷ group and whichcycloalkyl or cycloalkenyl may be optionally substituted by one or morehydroxyl or C₁₋₄ alkyl groups; R² represents hydrogen or C₁₋₄ alkyl; andJ¹, J² and J³ independently represent a moiety of formula (K):

wherein X¹ represents oxygen, NR¹¹ or sulphur, X² represents CH₂,oxygen, NR¹² or sulphur, m¹ represents an integer from 1 to 3 and m²represents an integer from 1 to 3, provided that m¹+m² is in the rangefrom 3 to 5, also provided that when both X¹ and X² represent oxygen,NR¹¹, NR¹² or sulphur, m¹ and m² must both not equal less than Z whereinK is optionally substituted by one or more —Y³-aryl, —Y³-heteroaryl,—Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₁ alkyl, —Y³—COOC₁₋₆ alkyl,Y³—COC₁₋₈ alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹⁵R¹⁶, —Y³—CONR¹⁵R¹⁶, hydroxy,oxo, —Y³—SO₂NR¹⁵R¹⁶, —Y³—SO₂C₁₋₆ alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl,—Y³-NR¹³C₁₋₆ alkyl, —Y³NR¹³SO₂C₁₋₆ alkyl, —Y³—NR¹³CONR¹⁵R¹⁶,—Y³—NR¹³COOR¹⁴ or —Y³—OCONR¹⁵R¹⁶ groups, and is optionally fused to amonocyclic aryl or heteroaryl ring.
 3. A compound of formula (I)according to claim 1 wherein R¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—,aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—,heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂-Y¹—, M-Y¹—, —Y¹-J¹, —Y¹—CO-J¹ or C₃₋₈cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl orcycloalkenyl may be optionally substituted by one or more hydroxyl orC₁₋₆ alkyl groups; R² represents hydrogen or C₁₋₆ alkyl; Z represents abond, CO, CR¹⁰R⁷(CH₂)_(n), CHR⁷(CH₂)_(n)O, CHR⁷(CH₂)_(n)S,CHR⁷(CH₂)_(n)OCO, CHR⁷(CH₂)_(n)CO; and J¹, J² and J³ independentlyrepresent a moiety of formula (K):

wherein X¹ represents oxygen, nitrogen, NR¹¹ or sulphur, X² representsCH₂, oxygen, nitrogen, NR¹² or sulphur, m¹ represents an integer from 1to 3, m² represents an integer from 1 to 3, provided that m¹+m² is inthe range from 3 to 5, also provided that when X² represents oxygen,nitrogen, NR¹² or sulphur, m¹ and m² must both not equal less than 2,wherein K is optionally substituted by one or more —Y³-aryl,—Y³-heteroaryl, —Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₄ alkyl, —Y³-COOC₁₋₆alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹⁵R¹⁶, —Y³—CONR¹⁵R¹⁶hydroxy, oxo, —Y³—SO₂NR¹⁵R¹⁶, —Y³—SO₂C₁, alkyl, —Y³—SO₂aryl, —Y³SO₂heteroaryl, —Y³—NR¹³C₁₋₄ alkyl, —Y³—NR¹³SO₂C₁₋₄ alkyl,—Y³—NR¹³CONR¹⁵R¹⁶, Y³—NR¹³COOR¹⁴ or —Y³—OCONR¹⁵R¹⁶ groups, and isoptionally fused to a monocyclic aryl or heteroaryl ring.
 4. A compoundof formula (I) according to any one of claims 1 to 3 wherein R¹represents aryl-Y¹— or heteroaryl-Y¹—.
 5. A compound of formula (I)according to claim 4 wherein R¹ represents optionally substitutedphenyl-Y¹— or tetrazolyl-Y¹— which phenyl and tetrazolyl may beoptionally substituted.
 6. A compound of formula (I) according to anyone of claims 1 to 5 wherein Y¹ represents —CH₂—.
 7. A compound offormula (I) according to claim 1 wherein X represents methylene.
 8. Acompound of formula (I) according to claim 1 wherein a and b bothrepresent
 1. 9. A compound of formula (I) according to claim 1 or claim3 wherein Z represents CO, CHR⁷(CH₂)_(n), CHR⁷(CH₂)_(n)O,CHR⁷(CH₂)_(n)S, CHR⁷(CH₂)_(n)OCO or CHR⁷(CH₂)_(n)CO.
 10. A compound offormula (I) according to claim 9 wherein Z represents CH₂.
 11. Acompound of formula (I) according to claim 1 wherein R⁶ representsphenyl optionally substituted with one or more halogen atoms.
 12. Acompound of formula (1) according to claim 11 wherein R⁶ represents3,4-dichlorophenyl.
 13. A compound of formula (I) according to any oneof claims 1 to 12 as described in Examples 1 to 189 or a salt or solvateof any one thereof.
 14. A compound of formula (I) according to claim 13which is 4-({[({[(2S)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}methyl)benzamideor a salt or solvate thereof.
 15. A compound of formula (I) according toclaim 13 which is N-{[(2S)-4-(3,4dichlorobenzyl)morpholin-2-yl]methyl}-N′-[(2-methyl-2H-tetraazol-5-yl)methyl]ureaor a salt or solvate thereof.
 16. A compound of formula (I) according toclaim 13 which is4-({[({[(2S)-4(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}methyl)N-methylbenzamideor a salt or solvate thereof.
 17. A pharmaceutical compositioncomprising a compound of formula (I) as defined in any one of claims 1to 16 or a pharmaceutically acceptable salt or solvate thereof inadmixture with one or more pharmaceutically acceptable diluents orcarriers.
 18. A compound of formula (I) as defined in any one of claims1 to 16 or a pharmaceutically acceptable salt or solvate thereof for useas a pharmaceutical.
 19. Use of a compound of formula (I) as defined inany one of claims 1 to 16 or a pharmaceutically acceptable salt orsolvate thereof in the manufacture of a medicament for the treatment ofinflammatory diseases.
 20. A method of treatment or prophylaxis ofinflammatory diseases eg. asthma which comprises administering to apatient an effective amount of a compound of formula (I) as defined inany one of claims 1 to 16 or a pharmaceutically acceptable salt orsolvate thereof.
 21. A process for preparing a compound of formula (I)as defined in any one of claims 1 to 16 which comprises: (a) reacting acompound of formula (II)

 wherein R¹, R², R³, R⁴, R⁵, X, a and b are as defined in claim 1, or aprotected derivative thereof, with a compound of formula L¹-Z-R⁶,wherein Z and R⁶ are as defined in claim 1 and L¹ represents a suitableleaving group; or (b) forming a compound of formula (I) wherein R²represents hydrogen which comprises reacting a compound of formula (III)

 wherein R³, R⁴, R⁵, R⁶, Z, X, a and b are as defined in claim 1, or aprotected derivative thereof, with a compound of formula R¹—N═C═O,wherein R¹ is as defined in claim 1; or (c) reacting a compound offormula (IV)

 wherein R³, R⁴, R⁵, R⁶, Z, X, a and b are as defined in claim 1 andL²represents a suitable leaving group, or a protected derivativethereof, with a compound of formula (V)

 wherein R¹ and R² are as defined in claim 1 or a protected derivativethereof; or (d) reacting a compound of formula (VI)

 wherein R¹ and R² are as defined in claim 1 and L³ represents asuitable leaving group, or a protected derivative thereof, with acompound of formula (III), or a protected derivative thereof, or (e)deprotecting a compound of formula (I) which is protected; or (f)interconversion of other compounds of formula (I).
 22. A process forpreparing a compound of formula (I) as defined in any one of claims 1 to16 which comprises: (g) forming a compound of formula (I) wherein R¹ andR² together with the nitrogen atom to which they are attached form agroup of formula J² wherein said nitrogen atom substitutes for either X¹or X² which comprises reacting a compound of formula (IV) or a protectedderivative thereof with a compound of formula J²H, provided that thecompound of formula J²H has a free —NH group; or (h) forming a compoundof formula (I) wherein Z represents CR¹⁰R⁷(CH₂)_(n), wherein R¹⁰represents hydrogen, which comprises reacting a compound of formula (II)or a protected derivative thereof with a compound of formulaR⁷CO(CH₂)_(n)R⁶, followed by reduction of the resultant imine; or (i)forming a compound of formula (I) wherein R¹ represents C₁₋₄alkyl-G-Y¹—, wherein G represents —NR¹⁸CO—, which comprises reacting acompound of formula (VII)

 or a protected derivative thereof wherein R², R³, R⁴, R⁵, R⁶, Y¹ X, Z,a and b are as defined in claim 1, with a compound of formula C₁₋₆alkyl-NHR¹⁸.
 23. A compound of formula (II)

wherein R¹, R², R³, R⁴, R⁵, X, a and b are as defined in claim 1, or aprotected derivative thereof, or a salt or solvate thereof.
 24. Acompound of formula (IV)

wherein R³, R⁴, R⁵, R⁶, Z, X, a and b are as defined in claim 1 and L²represents a suitable leaving group, or a protected derivative thereof,or a salt or solvate thereof.
 25. A compound of formula (VII)

wherein R², R³, R⁴, R⁵, R⁶, Y¹ X, Z, a and b are as defined in claim 1,or a protected derivative thereof, or a salt or solvate thereof.